- Email: [email protected]
Bone morphogenic protein-4: A potential novel target for preventing vein graft failure in coronary revascularization
Medical Hypotheses 81 (2013) 1025–1028
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Bone morphogenic protein-4: A potential novel target for preventing vein graft failure in coronary revascularization Jia Hu ⇑, Jing (Janice) Zhao Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 5 November 2012 Accepted 18 September 2013
a b s t r a c t Coronary artery bypass surgery is an effective and durable therapy in both acute coronary syndrome and chronic coronary stenotic disease refractory to pharmacological treatment. Despite rapid development in operation-specific technologies and secondary prevention measures, the benefits of surgical revascularization are largely limited by inadequate patency of one of the most commonly used conduits, namely the autologous saphenous vein. However, apart from antiplatelet and lipid-lowering drugs, no other pharmacologic agent has hitherto proven clinically effective in preventing short- and long-term vein graft failure. Aiming at a large number of known biomolecules, multiple promising strategies failed to translate their beneficial effects observed in animal models into the clinical settings. Bone morphogenic protein-4 (BMP4), originally identified as a mediator in bone formation, has been recently demonstrated to participate in the process of arterial post-injury remodeling. Existing evidence has demonstrated that BMP4 is closely involved in the pathogenesis of thrombus formation, neointimal hyperplasia and superimposed atherosclerosis, all of which significantly contribute to arterial stenotic lesions. Although the post-injury responses inherent to arterial and venous vessel are unique, they share common elements and present with similar physiologic characteristics and clinical sequelae. Therefore, with regard to the multifaceted effects of BMP4 in regulating arterial wall remodeling, we hypothesize that BMP4 may play an important role in mediating the pathological responses of the venous wall to the arterial circulation. If our hypothesis is demonstrated correct, BMP4 inhibition could presumably serve as a novel strategy for preventing vein graft failure in coronary revascularization. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction With the ever-growing threat of ischemic heart disease worldwide, the past decades had witnessed continually advancement of coronary artery bypass grafting (CABG) and percutaneous coronary intervention. Despite the increasing use of intracoronary stents and a debate over the most appropriate revascularization strategies, current evidence maintains the use of CABG as an optimal therapy for patients with unprotected left-main and multivessel coronary lesions [1,2]. Unfortunately, however, the long-term success of surgical revascularization is largely limited by the inadequate patency rate of one of the most commonly used conduits, namely the autologous saphenous vein [1,3]. Saphenous vein graft failure represents a clinical entity affected by a complex series of interrelated factors, including surgical techniques, patient-specific risk factors, hemodynamics and inherent biologic responses. Although the underlying mechanisms are still incompletely elucidated, thrombosis, neointimal hyperplasia and superimposed atherosclerosis are well-recognized as the prime
⇑ Corresponding author. Tel./fax: +86 028 85421833. E-mail address: [email protected] (J. Hu). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.09.023
culprits which, logically, have gained the most attention of current therapeutic explorations [3,4]. However, apart from antiplatelet and lipid-lowering therapy, no other intervention has hitherto proven clinically effective in improving short- or long-term vein graft patency [5]. Aiming at a variety of known biomolecules, novel pharmacological agents, drug-releasing external supports and gene therapy failed to translate their beneficial effects observed in animal models into the clinical settings [3–6]. Given the persistent increase in the incidence of CABG patients living with symptomatic vein graft diseases that need repeat revascularization procedures [2–4], further investigations of novel molecules and associated pathways [3–7] that can be best targeted are urgently required. Bone morphogenic protein-4 (BMP4) is one of the structurally related members of transforming growth factor b superfamily, and its activities are originally identified in human embryonic development, differentiation, and endochondral formation [8]. Recently, BMP4 has been proposed to play a significant role in vascular injury responses and in the development of inflammation and atherosclerotic lesions within the arterial wall. Overexpression of BMP4 could lead to endothelial dysfunction and induce arterial endothelial cells (AECs) apoptosis through reactive oxygen species (ROS)-dependent pathways [9,10]. Such an increase of BMP4 level
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J. Hu, Jing (Janice) Zhao / Medical Hypotheses 81 (2013) 1025–1028
was also demonstrated to enhance intercellular adhesion molecules expression and facilitate circulating leukocytes infiltration, a critical early step in atherogenesis [11]. Moreover, BMP4 was found to be highly effective in promoting the activation of vascular smooth muscle cells (VSMCs) which contributes significantly to vascular neointima formation and medial thickening [12,13]. Nevertheless, the involvement of BMP4 in the process of vein graft remodeling remain largely unknown, and BMP4-activated pathways that may result in venous wall over-thickening are not well characterized. With regard to the proinflammatory, proatherogenic and pro-hyperplastic effects of BMP4 in regulating arterial post-injury remodeling, we hypothesize that BMP4 might play an important role in promoting the pathological responses of the venous wall to the arterial circulation, and BMP4 inhibition could presumably serve as a novel strategy for preventing vein graft failure in coronary revascularization. The hypothesis BMP4 might promote and accelerate the progression of vein graft failure. The hypothesis stems from lines of evidence demonstrating the vigorous interactions between BMP4 and the living components within the vascular wall, including endothelial cells, VSMCs and fibroblasts. Furthermore, the multifaceted effects of BMP4 in enhancing inflammatory responses and subsequent atherogenesis might also contribute to the development of vein graft stenotic diseases (Fig. 1). BMP4 and the impairment of endothelial barrier function All grafted saphenous veins initially experience abrupt hemodynamic changes in elevated arterial blood pressure, shear stress, wall tension and pulsatile flow [3,6]. The geometric and compliant mismatches between vein grafts and recipient coronary arteries would lead to distinct flow discrepancies, particularly prominent
at the site of luminal irregularities (i.e. anastomosis and venous valves) [6]. As a mechanosensitive autocrine cytokine, BMP4 is easily detected in human and mouse AECs cultured in disturbed flow [11]. Overexpression of BMP4 in endothelial cells stimulates expression and activity of nicotinamide adenine dinucteotide phosphate oxidases, which causes overproduction of ROS, upregulated intercellular adhesion molecule expression, and subsequent increased monocytes adhesivity. The endothelial origin production of ROS induced by BMP4 was responsible for the decreased levels of the endothelial-derived anti-thrombotic biofactors (principally nitric oxide, prostacyclin and heparin-like substance) and impaired endothelium-dependent relaxations [9]. Moreover, BMP4 has been demonstrated to directly induce endothelium apoptosis through oxidative stress-dependent p38 mitogen-activated protein kinase and c-Jun N-terminal kinases pathways in human and rat arteries in vitro [10]. Taken together, upregulated BMP4 expression is linked to the impairment of the functional and structural integrity of the endothelial layer. The damaged endothelium quite rapidly acts as a theatre for platelet aggregation and subsequent coagulant cascades, which lead to acute thrombosis and predispose to early vein graft failure.
The interactions between BMP4 and VSMCs and fibroblasts Pathological intimal thickening characterized by migrating VSMCs and fibroblasts proliferation along with extracellular matrix (ECM) deposition is the basis for the mid- and long-term graft failure. Existing evidence has indicated that BMP4 signaling pathway plays an important role in the development of arterial proliferative disorders [12–14]. As demonstrated in an in vitro study, Yang et al. [11] found induction of exogenous BMP4 in cultured peripheral pulmonary artery could enhance medial VSMCs proliferation/survival through p38 mitogen-activated protein kinase-dependent pathway. Similarly in a mouse of pulmonary hypertension model [12], pulmonary AECs secrete BMP4 in response to hypoxia and
Fig. 1. Schematic diagram illustrating the potential mechanisms of bone morphogenic protein 4 (BMP4)-related negative (inward) vein graft remodeling. Overexpression of BMP4 induced by disturbed flow leads to impaired endothelial barrier function, activated vascular smooth muscle cells and fibroblasts, as well as enhanced atherogenesis. ECs, endothelial cells; VSMCs, vascular smooth muscle cells; ECM, extracellular matrix.
J. Hu, Jing (Janice) Zhao / Medical Hypotheses 81 (2013) 1025–1028
further enhance proliferation and migration of VSMCs in a BMP4dependent fashion. Moreover, Kang et al. demonstrated that BMP4 could promote VSMCs contractility by activating microRNA-21 and its downstream proteins [15]. Although the contributory role of VSMCs contraction in vein graft constriction is difficult to evaluate, it is speculated that inadequate relaxation of the venous wall caused by medial VSMCs excessive contraction may result in limited intraluminal blood flow, which contributes significantly to thrombus formation within days after implantation. It has also been shown that BMP4 could induce differentiation of fetal lung fibroblasts into smooth muscle-like cells [14], namely myofibroblasts, which are functionally migratable and are responsible for abundant extracellular matrix synthesis and deposition in the subendothelial space [16]. Although the biological responses inherent to arterial and venous vessel are different, they share common elements involved in the pathogenesis of neointima formation and medial thickening. Thus, it is conceivable that aberrant BMP4 signaling may promote negative (inward) vein graft remodeling through the activation of medial VSMCs and adventitial fibroblasts. BMP4 and atherogenesis On the basis of thickened intima, superimposed accelerated atherosclerosis is the major determinant of vein graft failure one year after coronary surgery. Recent experimental studies have proposed BMP4 as a mediator in the development of inflammation and subsequent atherogenesis. Support for this suggestion is gained from the observation that in AECs overlying foam cells (an early form of atherosclerotic lesions) selective overexpression of BMP4 occurs concurrently with enhanced inflammatory responses [17]. Highly expressed BMP4 protein was further detected in human atherosclerotic plaques from abdominal aortas [18]. In particular, exogenous administration or inhibition of BMP4 in endothelial cells has been found to stimulate or suppress the induction of intercellular adhesion molecule-1 and the transendothelial invasion of circulating monocytes [17,19]. As monocytes-derived foam cells would eventually become the epicenter of the atherosclerotic plaques, it is reasonable to speculate that BMP4-activated pathways participate in mediating the formation of atherosclerosis. The direct proof of the involvement of BMP4 in mediating the pathogenesis of vascular atherosclerotic diseases has been provided by two recent studies. Yao et al. demonstrated that inhibition of BMP4 expression in a mice hyperlipidemia model significantly reduced aortic atherosclerotic lesions and calcification [20]. On the contrary, genetically manipulating one of the BMP receptors in a mice hypercholesteolemia model could significantly cause endothelial inflammation and atherosclerosis [21]. Furthermore, apart from BMP4 and its specific receptors alone, BMP4-induced overproduction of ROS is also demonstrated to initiate and enhance inflammatory and atherogenic cascades, stimulating adhesion molecules expression on the endothelial surface in a NF-jB-dependent manner, resulting in monocytes infiltration and transformation into foam cells [22].
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atherosclerosis-predisposing diseases and an increased propensity for graft failure [23,24]. Despite the incomplete understanding of the exact mechanisms, excessive oxidative stress is generally regarded as the common cause for a series of proliferative and atherogenic events in the pathogenesis of vein graft stenotic lesions. Considering the close interaction between BMP4 and ROS, we have reasons to believe that a marked increase of BMP4 in saphenous veins harvested from patients with metabolic diseases may preclude a higher chance of long-term graft failure. Actually, the levels of BMP4 expression in arteries and ROS expression in veins from hypertensive, dyslipidemia or diabetic patients were significantly higher than those from normal subjects [11,25]. More recently, Hu and colleagues also demonstrated an important role of the increased BMP4 expression and related ROS overproduction in the development of hyperglycemia-induced venous endothelial dysfunction in human and porcine [26]. Therefore, in other words, the cellular and molecular programs that stimulate the negative vein graft remodeling may have already been pre-engineered by BMP4 at ‘‘time zero’’. As far as the clinical situation and our hypothesis are concerned, BMP4 inhibition appears to be promising in preventing vein graft failure in the settings of coronary revascularization. Firstly, treatment of harvested veins with BMP4 inhibitor prior to implantation (eg. gene transfer or pharmacological interventions) may counteract the harmful effects elicited by the pre-existed diseases and potentially decrease the susceptibility of the grafted veins remodeling through BMP4-activated pathways. Secondly, nowadays, percutaneous coronary intervention has established itself as the treatment of choice for treating extremely high-risk or inoperable patients with aggressive vein grafts diseases after CABG. However, even with evolved design and biomaterials, specific stent platforms, polymers and coating drugs that are more appropriate in tackling vein graft atherosclerosis-related stenosis remain to be addressed at this time [27]. In view of the pro-hyperplastic and pro-atherogenic effects of BMP4, the therapeutic potential of releasing BMP4 inhibitor in a stable and controllable manner through the internal stents or even external supports [6] deserves further investigation. In conclusion, the hypothesis that BMP4 is associated with or even responsible for the development of short and long-term vein graft failure is reasonable. Further exploration of the specific role of BMP4 in promoting the progression of vein graft stenotic disease may open new horizons in therapeutic interventions aiming at improving long-term vein graft patency in post-CABG patients. Sources of support This work was supported by the National Natural Science Foundation of China (No. 81300155). Conflict of interest All authors disclose any financial and personal relationships with other people or organizations that could inappropriately influence the work. The Authors declare no conflict of interest.
Clinical relevance of the hypothesis and discussion References In the ‘‘real world’’, saphenous veins harvested from legs are seldom disease-free. Apart from the inherent pathological changes (eg. venous varicosities), patient-specific risk factors, including hyperlipidemia, diabetes, hypertension and obesity etc., significantly influence the quality of the conduits and play an important role in determining the durability and longevity of vein grafts after bypass surgery. Both clinical and experimental studies clearly indicate a causal relationship between these
[1] Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, et al. 2011 ACCF/ AHA guideline for coronary artery bypass graft surgery: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation 2011;124(23):e652–735. [2] Weintraub WS, Grau-Sepulveda MV, Weiss JM, O’Brien SM, Peterson ED, Kolm P, et al. Comparative effectiveness of revascularization strategies. N Engl J Med 2012;366(16):1467–76. [3] Wan S, George SJ, Berry C, Baker AH. Vein graft failure: current clinical practice and potential for gene therapeutics. Gene Ther 2012;19(6):630–6.
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[4] Harskamp RE, Lopes RD, Baisden CE, de Winter RJ, Alexander JH. Saphenous vein graft failure after coronary artery bypass surgery: pathophysiology, management, and future directions. Ann Surg 2013;257(5):824–33. [5] Jeremy JY, Zacharowski K, Shukla N, Wan S. Pharmacological strategies aimed at reducing complications associated with coronary artery bypass graft surgery. Curr Opin Pharmacol 2012;12(2):111–3. [6] Hu J, Wan S. External support in preventing vein graft failure. Asian Cardiovasc Thorac Ann 2012;20(5):615–22. [7] Zheng H, Xue S, Lian F, Wang YY. A novel promising therapy for vein graft restenosis: overexpressed Nogo-B induces vascular smooth muscle cell apoptosis by activation of the JNK/p38 MAPK signaling pathway. Med Hypotheses 2011;77(2):278–81. [8] Leong LM, Brickell PM. Bone morphogenic protein-4. Int J Biochem Cell Biol 1996;28(12):1293–6. [9] Wong WT, Tian XY, Chen Y, et al. Bone morphogenic protein-4 impairs endothelial function through oxidative stress-dependent cyclooxygenase-2 upregulation: implications on hypertension. Circ Res 2010;107(8):984–91. [10] Tian XY, Yung LH, Wong WT, et al. Bone morphogenic protein-4 induces endothelial cell apoptosis through oxidative stress-dependent p38MAPK and JNK pathway. J Mol Cell Cardiol 2012;52(1):237–44. [11] Chang K, Weiss D, Suo J, Vega JD, Giddens D, Taylor WR, et al. Bone morphogenic protein inhibitors are coexpressed with bone morphogenic protein 4 in endothelial cells exposed to unstable flow in vitro in mouse aortas and in human coronary arteries: role of bone morphogenic protein inhibitors in inflammation and atherosclerosis. Circulation 2007;116(11):1258–66. [12] Yang X, Long L, Southwood M, Rudarakanchana N, Upton PD, Jeffery TK, et al. Dysfunctional Smad signaling contributes to abnormal smooth muscle cell proliferation in familial pulmonary arterial hypertension. Circ Res 2005;96(10):1053–63. [13] Frank DB, Abtahi A, Yamaguchi DJ, Manning S, Shyr Y, Pozzi A, et al. Bone morphogenetic protein 4 promotes pulmonary vascular remodeling in hypoxic pulmonary hypertension. Circ Res 2005;97(5):496–504. [14] Jeffery TK, Upton PD, Trembath RC, Morrell NW. BMP4 inhibits proliferation and promotes myocyte differentiation of lung fibroblasts via Smad1 and JNK pathways. Am J Physiol Lung Cell Mol Physiol 2005;288(2):L370–378. [15] Kang H, Davis-Dusenbery BN, Nguyen PH, Lal A, Lieberman J, Van Aelst L, et al. Bone morphogenetic protein 4 promotes vascular smooth muscle contractility by activating microRNA-21 (miR-21), which down-regulates expression of family of dedicator of cytokinesis (DOCK) proteins. J Biol Chem 2012;287(6):3976–86.
[16] Sartore S, Chiavegato A, Faggin E, Franch R, Puato M, Ausoni S, et al. Contribution of adventitial fibroblasts to neointima formation and vascular remodeling: from innocent bystander to active participant. Circ Res 2001;89(12):1111–21. [17] Sorescu GP, Sykes M, Weiss D, Platt MO, Saha A, Hwang J, et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress stimulates an inflammatory response. J Biol Chem 2003;278(33):31128–35. [18] Dhore CR, Cleutjens JP, Lutgens E, Cleutjens KB, Geusens PP, Kitslaar PJ, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol 2001;21(12):1998–2003. [19] Sorescu GP, Song H, Tressel SL, Hwang J, Dikalov S, Smith DA, et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase. Circ Res 2004;95(8):773–9. [20] Yao Y, Bennett BJ, Wang X, Rosenfeld ME, Giachelli C, Lusis AJ, et al. Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification. Circ Res 2010;107(4):485–94. [21] Kim CW, Song H, Kumar S, Nam D, Kwon HS, Chang KH, et al. Antiinflammatory and antiatherogenic role of BMP receptor II in endothelial cells. Arterioscler Thromb Vasc Biol 2013;33(6):1350–9. [22] Jo H, Song H, Mowbray A. Role of NADPH oxidases in disturbed flow- and BMP4- induced inflammation and atherosclerosis. Antioxid Redox Signal 2006;8(9–10):1609–19. [23] Sarjeant JM, Rabinovitch M. Understanding and treating vein graft atherosclerosis. Cardiovasc Pathol 2002;11(5):263–71. [24] Singh SK, Desai ND, Petroff SD, et al. The impact of diabetic status on coronary artery bypass graft patency: insights from the radial artery patency study. Circulation 2008;118(Suppl. 14):S222–225. [25] Chello M, Spadaccio C, Lusini M, Covino E, Blarzino C, De Marco F, et al. Advanced glycation end products in diabetic patients with optimized glycaemic control and their effects on endothelial reactivity: possible implications in venous graft failure. Diabetes Metab Res Rev 2009;25(5):420–6. [26] Hu J, Liu J, Kwok MW, Wong RH, Huang Y, Wan S. Bone morphogenic protein-4 contributes to venous endothelial dysfunction in patients with diabetes undergoing coronary revascularization. Ann Thorac Surg 2013;95(4):1331–9. [27] Escaned J. Secondary revascularization after CABG surgery. Nat Rev Cardiol 2012;9(9):540–9.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Bone morphogenic protein-4: A potential novel target for preventing vein graft failure in coronary revascularization Jia Hu ⇑, Jing (Janice) Zhao Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
a r t i c l e
i n f o
Article history: Received 5 November 2012 Accepted 18 September 2013
a b s t r a c t Coronary artery bypass surgery is an effective and durable therapy in both acute coronary syndrome and chronic coronary stenotic disease refractory to pharmacological treatment. Despite rapid development in operation-specific technologies and secondary prevention measures, the benefits of surgical revascularization are largely limited by inadequate patency of one of the most commonly used conduits, namely the autologous saphenous vein. However, apart from antiplatelet and lipid-lowering drugs, no other pharmacologic agent has hitherto proven clinically effective in preventing short- and long-term vein graft failure. Aiming at a large number of known biomolecules, multiple promising strategies failed to translate their beneficial effects observed in animal models into the clinical settings. Bone morphogenic protein-4 (BMP4), originally identified as a mediator in bone formation, has been recently demonstrated to participate in the process of arterial post-injury remodeling. Existing evidence has demonstrated that BMP4 is closely involved in the pathogenesis of thrombus formation, neointimal hyperplasia and superimposed atherosclerosis, all of which significantly contribute to arterial stenotic lesions. Although the post-injury responses inherent to arterial and venous vessel are unique, they share common elements and present with similar physiologic characteristics and clinical sequelae. Therefore, with regard to the multifaceted effects of BMP4 in regulating arterial wall remodeling, we hypothesize that BMP4 may play an important role in mediating the pathological responses of the venous wall to the arterial circulation. If our hypothesis is demonstrated correct, BMP4 inhibition could presumably serve as a novel strategy for preventing vein graft failure in coronary revascularization. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction With the ever-growing threat of ischemic heart disease worldwide, the past decades had witnessed continually advancement of coronary artery bypass grafting (CABG) and percutaneous coronary intervention. Despite the increasing use of intracoronary stents and a debate over the most appropriate revascularization strategies, current evidence maintains the use of CABG as an optimal therapy for patients with unprotected left-main and multivessel coronary lesions [1,2]. Unfortunately, however, the long-term success of surgical revascularization is largely limited by the inadequate patency rate of one of the most commonly used conduits, namely the autologous saphenous vein [1,3]. Saphenous vein graft failure represents a clinical entity affected by a complex series of interrelated factors, including surgical techniques, patient-specific risk factors, hemodynamics and inherent biologic responses. Although the underlying mechanisms are still incompletely elucidated, thrombosis, neointimal hyperplasia and superimposed atherosclerosis are well-recognized as the prime
⇑ Corresponding author. Tel./fax: +86 028 85421833. E-mail address: [email protected] (J. Hu). 0306-9877/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2013.09.023
culprits which, logically, have gained the most attention of current therapeutic explorations [3,4]. However, apart from antiplatelet and lipid-lowering therapy, no other intervention has hitherto proven clinically effective in improving short- or long-term vein graft patency [5]. Aiming at a variety of known biomolecules, novel pharmacological agents, drug-releasing external supports and gene therapy failed to translate their beneficial effects observed in animal models into the clinical settings [3–6]. Given the persistent increase in the incidence of CABG patients living with symptomatic vein graft diseases that need repeat revascularization procedures [2–4], further investigations of novel molecules and associated pathways [3–7] that can be best targeted are urgently required. Bone morphogenic protein-4 (BMP4) is one of the structurally related members of transforming growth factor b superfamily, and its activities are originally identified in human embryonic development, differentiation, and endochondral formation [8]. Recently, BMP4 has been proposed to play a significant role in vascular injury responses and in the development of inflammation and atherosclerotic lesions within the arterial wall. Overexpression of BMP4 could lead to endothelial dysfunction and induce arterial endothelial cells (AECs) apoptosis through reactive oxygen species (ROS)-dependent pathways [9,10]. Such an increase of BMP4 level
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was also demonstrated to enhance intercellular adhesion molecules expression and facilitate circulating leukocytes infiltration, a critical early step in atherogenesis [11]. Moreover, BMP4 was found to be highly effective in promoting the activation of vascular smooth muscle cells (VSMCs) which contributes significantly to vascular neointima formation and medial thickening [12,13]. Nevertheless, the involvement of BMP4 in the process of vein graft remodeling remain largely unknown, and BMP4-activated pathways that may result in venous wall over-thickening are not well characterized. With regard to the proinflammatory, proatherogenic and pro-hyperplastic effects of BMP4 in regulating arterial post-injury remodeling, we hypothesize that BMP4 might play an important role in promoting the pathological responses of the venous wall to the arterial circulation, and BMP4 inhibition could presumably serve as a novel strategy for preventing vein graft failure in coronary revascularization. The hypothesis BMP4 might promote and accelerate the progression of vein graft failure. The hypothesis stems from lines of evidence demonstrating the vigorous interactions between BMP4 and the living components within the vascular wall, including endothelial cells, VSMCs and fibroblasts. Furthermore, the multifaceted effects of BMP4 in enhancing inflammatory responses and subsequent atherogenesis might also contribute to the development of vein graft stenotic diseases (Fig. 1). BMP4 and the impairment of endothelial barrier function All grafted saphenous veins initially experience abrupt hemodynamic changes in elevated arterial blood pressure, shear stress, wall tension and pulsatile flow [3,6]. The geometric and compliant mismatches between vein grafts and recipient coronary arteries would lead to distinct flow discrepancies, particularly prominent
at the site of luminal irregularities (i.e. anastomosis and venous valves) [6]. As a mechanosensitive autocrine cytokine, BMP4 is easily detected in human and mouse AECs cultured in disturbed flow [11]. Overexpression of BMP4 in endothelial cells stimulates expression and activity of nicotinamide adenine dinucteotide phosphate oxidases, which causes overproduction of ROS, upregulated intercellular adhesion molecule expression, and subsequent increased monocytes adhesivity. The endothelial origin production of ROS induced by BMP4 was responsible for the decreased levels of the endothelial-derived anti-thrombotic biofactors (principally nitric oxide, prostacyclin and heparin-like substance) and impaired endothelium-dependent relaxations [9]. Moreover, BMP4 has been demonstrated to directly induce endothelium apoptosis through oxidative stress-dependent p38 mitogen-activated protein kinase and c-Jun N-terminal kinases pathways in human and rat arteries in vitro [10]. Taken together, upregulated BMP4 expression is linked to the impairment of the functional and structural integrity of the endothelial layer. The damaged endothelium quite rapidly acts as a theatre for platelet aggregation and subsequent coagulant cascades, which lead to acute thrombosis and predispose to early vein graft failure.
The interactions between BMP4 and VSMCs and fibroblasts Pathological intimal thickening characterized by migrating VSMCs and fibroblasts proliferation along with extracellular matrix (ECM) deposition is the basis for the mid- and long-term graft failure. Existing evidence has indicated that BMP4 signaling pathway plays an important role in the development of arterial proliferative disorders [12–14]. As demonstrated in an in vitro study, Yang et al. [11] found induction of exogenous BMP4 in cultured peripheral pulmonary artery could enhance medial VSMCs proliferation/survival through p38 mitogen-activated protein kinase-dependent pathway. Similarly in a mouse of pulmonary hypertension model [12], pulmonary AECs secrete BMP4 in response to hypoxia and
Fig. 1. Schematic diagram illustrating the potential mechanisms of bone morphogenic protein 4 (BMP4)-related negative (inward) vein graft remodeling. Overexpression of BMP4 induced by disturbed flow leads to impaired endothelial barrier function, activated vascular smooth muscle cells and fibroblasts, as well as enhanced atherogenesis. ECs, endothelial cells; VSMCs, vascular smooth muscle cells; ECM, extracellular matrix.
J. Hu, Jing (Janice) Zhao / Medical Hypotheses 81 (2013) 1025–1028
further enhance proliferation and migration of VSMCs in a BMP4dependent fashion. Moreover, Kang et al. demonstrated that BMP4 could promote VSMCs contractility by activating microRNA-21 and its downstream proteins [15]. Although the contributory role of VSMCs contraction in vein graft constriction is difficult to evaluate, it is speculated that inadequate relaxation of the venous wall caused by medial VSMCs excessive contraction may result in limited intraluminal blood flow, which contributes significantly to thrombus formation within days after implantation. It has also been shown that BMP4 could induce differentiation of fetal lung fibroblasts into smooth muscle-like cells [14], namely myofibroblasts, which are functionally migratable and are responsible for abundant extracellular matrix synthesis and deposition in the subendothelial space [16]. Although the biological responses inherent to arterial and venous vessel are different, they share common elements involved in the pathogenesis of neointima formation and medial thickening. Thus, it is conceivable that aberrant BMP4 signaling may promote negative (inward) vein graft remodeling through the activation of medial VSMCs and adventitial fibroblasts. BMP4 and atherogenesis On the basis of thickened intima, superimposed accelerated atherosclerosis is the major determinant of vein graft failure one year after coronary surgery. Recent experimental studies have proposed BMP4 as a mediator in the development of inflammation and subsequent atherogenesis. Support for this suggestion is gained from the observation that in AECs overlying foam cells (an early form of atherosclerotic lesions) selective overexpression of BMP4 occurs concurrently with enhanced inflammatory responses [17]. Highly expressed BMP4 protein was further detected in human atherosclerotic plaques from abdominal aortas [18]. In particular, exogenous administration or inhibition of BMP4 in endothelial cells has been found to stimulate or suppress the induction of intercellular adhesion molecule-1 and the transendothelial invasion of circulating monocytes [17,19]. As monocytes-derived foam cells would eventually become the epicenter of the atherosclerotic plaques, it is reasonable to speculate that BMP4-activated pathways participate in mediating the formation of atherosclerosis. The direct proof of the involvement of BMP4 in mediating the pathogenesis of vascular atherosclerotic diseases has been provided by two recent studies. Yao et al. demonstrated that inhibition of BMP4 expression in a mice hyperlipidemia model significantly reduced aortic atherosclerotic lesions and calcification [20]. On the contrary, genetically manipulating one of the BMP receptors in a mice hypercholesteolemia model could significantly cause endothelial inflammation and atherosclerosis [21]. Furthermore, apart from BMP4 and its specific receptors alone, BMP4-induced overproduction of ROS is also demonstrated to initiate and enhance inflammatory and atherogenic cascades, stimulating adhesion molecules expression on the endothelial surface in a NF-jB-dependent manner, resulting in monocytes infiltration and transformation into foam cells [22].
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atherosclerosis-predisposing diseases and an increased propensity for graft failure [23,24]. Despite the incomplete understanding of the exact mechanisms, excessive oxidative stress is generally regarded as the common cause for a series of proliferative and atherogenic events in the pathogenesis of vein graft stenotic lesions. Considering the close interaction between BMP4 and ROS, we have reasons to believe that a marked increase of BMP4 in saphenous veins harvested from patients with metabolic diseases may preclude a higher chance of long-term graft failure. Actually, the levels of BMP4 expression in arteries and ROS expression in veins from hypertensive, dyslipidemia or diabetic patients were significantly higher than those from normal subjects [11,25]. More recently, Hu and colleagues also demonstrated an important role of the increased BMP4 expression and related ROS overproduction in the development of hyperglycemia-induced venous endothelial dysfunction in human and porcine [26]. Therefore, in other words, the cellular and molecular programs that stimulate the negative vein graft remodeling may have already been pre-engineered by BMP4 at ‘‘time zero’’. As far as the clinical situation and our hypothesis are concerned, BMP4 inhibition appears to be promising in preventing vein graft failure in the settings of coronary revascularization. Firstly, treatment of harvested veins with BMP4 inhibitor prior to implantation (eg. gene transfer or pharmacological interventions) may counteract the harmful effects elicited by the pre-existed diseases and potentially decrease the susceptibility of the grafted veins remodeling through BMP4-activated pathways. Secondly, nowadays, percutaneous coronary intervention has established itself as the treatment of choice for treating extremely high-risk or inoperable patients with aggressive vein grafts diseases after CABG. However, even with evolved design and biomaterials, specific stent platforms, polymers and coating drugs that are more appropriate in tackling vein graft atherosclerosis-related stenosis remain to be addressed at this time [27]. In view of the pro-hyperplastic and pro-atherogenic effects of BMP4, the therapeutic potential of releasing BMP4 inhibitor in a stable and controllable manner through the internal stents or even external supports [6] deserves further investigation. In conclusion, the hypothesis that BMP4 is associated with or even responsible for the development of short and long-term vein graft failure is reasonable. Further exploration of the specific role of BMP4 in promoting the progression of vein graft stenotic disease may open new horizons in therapeutic interventions aiming at improving long-term vein graft patency in post-CABG patients. Sources of support This work was supported by the National Natural Science Foundation of China (No. 81300155). Conflict of interest All authors disclose any financial and personal relationships with other people or organizations that could inappropriately influence the work. The Authors declare no conflict of interest.
Clinical relevance of the hypothesis and discussion References In the ‘‘real world’’, saphenous veins harvested from legs are seldom disease-free. Apart from the inherent pathological changes (eg. venous varicosities), patient-specific risk factors, including hyperlipidemia, diabetes, hypertension and obesity etc., significantly influence the quality of the conduits and play an important role in determining the durability and longevity of vein grafts after bypass surgery. Both clinical and experimental studies clearly indicate a causal relationship between these
[1] Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, et al. 2011 ACCF/ AHA guideline for coronary artery bypass graft surgery: a report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation 2011;124(23):e652–735. [2] Weintraub WS, Grau-Sepulveda MV, Weiss JM, O’Brien SM, Peterson ED, Kolm P, et al. Comparative effectiveness of revascularization strategies. N Engl J Med 2012;366(16):1467–76. [3] Wan S, George SJ, Berry C, Baker AH. Vein graft failure: current clinical practice and potential for gene therapeutics. Gene Ther 2012;19(6):630–6.
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