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Is dysfunction of the tissue plasminogen activator (tPA)-plasmin pathway a link between major depression and cardiovascular disease?
Medical Hypotheses 72 (2009) 166–168
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Is dysfunction of the tissue plasminogen activator (tPA)-plasmin pathway a link between major depression and cardiovascular disease? Sheue-Jane Hou a, Feng-Chang Yen a, Shih-Jen Tsai b,c,* a
Division of Psychiatry, Cheng-Hsin Rehabilitation and Medical Center, Taipei, Taiwan, ROC Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan, ROC c Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC b
a r t i c l e
i n f o
Article history: Received 25 June 2008 Accepted 10 September 2008
s u m m a r y Epidemiological, genetic and clinical studies have demonstrated an association between major depressive disorder (MDD) and cardiovascular disease (CVD). For example, MDD is a risk factor for the development of CVD, while around one fifth of patients with CVD have MDD and a significantly larger percentage have subsyndromal symptoms of depression. Furthermore, patients with CVD and depression have an increased risk of future cardiac events compared to similar cohorts without depression, independent of baseline cardiac dysfunction. Despite evidence that CVD and MDD are epidemiologically linked, the cause of this correlation is still unknown. Several risk factors including physical and psychological stress, smoking, physical inactivity and inflammation have been proposed to mediate the interaction between MDD and CVD. The tissue-type plasminogen activator (tPA)-plasminogen proteolytic cascade is widely expressed in the brain. Accumulating evidence from preclinical and clinical studies suggests that tPA and its inhibitor, plasminogen activator inhibitor-1, are related to stress reaction and depression. In addition, brain-derived neurotrophic factor (BDNF) is important for the pathogenesis of MDD and the tPAplasminogen proteolytic cascade has been implicated in the cleavage of proBDNF to BDNF in the brain, by which the direction of BDNF action is controlled. Thus, it is proposed that tPA-plasmin pathway dysfunction may play a role in the link between MDD and CVD. Future study of the components in the tPAplasminogen system in CVD patients comorbid with MDD may lead to new, potentially important insights into the link between MDD and CVD, and might also contribute to novel strategies for the management of these two common and devastating diseases. Ó 2008 Elsevier Ltd. All rights reserved.
Worldwide, major depressive disorder (MDD) and cardiovascular disease (CVD) are two of the most prevalent health problems and are leading cause of disability. There is a substantial body of evidence suggesting a strong relation between MDD and CVD. For example, both epidemiological and clinical studies have demonstrated that subjects initially free of CVD but with depression have a 2-fold to 4-fold increased risk of developing CVD independent of other known risk factors [1–3]. In addition, depression is also an independent predictor of poor outcome following a cardiac event [4,5]. In turn, CVD patients often develop MDD. Gonzalez et al. found MDD in 23% of patients with coronary artery disease [6]. Despite evidence that MDD and CVD are epidemiologically linked, the cause of this correlation is still unknown. Hypotheses regarding the link between MDD and CVD include physical and psychological stress, smoking, physical inactivity and dysregulation of inflammatory function [for review see Refs. [7,8]]. In addi-
* Corresponding author. Address: Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Shih-Pai Road, Sector 2, 11217, Taipei, Taiwan. Tel.: +886 2 28757027x276; fax: +886 2 28725643. E-mail address: [email protected] (S.-J. Tsai). 0306-9877/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.09.009
tion, other traditional CVD risk factors (including diabetes, obesity and hypertension) have also been associated with MDD [9–11]. Here, from studies of thrombolytic factors in MDD and the neurotropic model of MDD [12], we propose that dysfunction of the tissue plasminogen activator (tPA)-plasmin pathway could also link MDD and CVD. tPA is a highly specific serine proteinase that converts the plasminogen zymogen to the active serine protease plasmin. tPA is found in the blood, where its primary function is as a thrombolytic enzyme, and, in the brain, it promotes events associated with synaptic plasticity and cell death in a number of settings, such as neurodegeneration and seizures [13]. Since thrombosis is involved in the pathogenesis of CVD [14] and the tPA-plasmin proteolytic cascade is known to be important for thrombolysis [15], there is abundant evidence that the tPA-plasmin pathway is involved in the pathogenesis of CVD [for review see Ref. [16]]. Furthermore, decreased thrombolysis capacity has been identified prospectively as having an important role in the development of CVD [17]. Recently, an association between the tPA-plasmin proteolytic cascade and MDD has been demonstrated in clinical as well as animal studies. In the adult murine brain, components of the
S.-J. Hou et al. / Medical Hypotheses 72 (2009) 166–168
tPA-plasmin system are abundantly expressed in areas such as the hippocampus [18], a region important for the pathogenesis of MDD. Accumulating evidence regarding the expression and role of the tPA pathway also suggests that this pathway has a key role in the biology of emotions [for review see Ref. [19]]. Stress is a common precipitating factor for MDD and tPA is also critical for the stress reaction. In mice subjected to acute restraint stress, tPA activity was rapidly up-regulated in the amygdala, while mice in which the tPA gene had been disrupted did not show anxiety after repeated stress [20]. In a clinical study, patients with depression showed significantly lower plasma tPA concentrations than normal persons [21]. In addition to direct measures of tPA levels in depression, tPA has been hypothesised to be linked to MDD through its extracellular proteolysis function [22]. Briefly, evidence from animal and human studies has suggested that brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family known to regulate neuronal plasticity and survival, may play an important role in the pathogenesis of MDD and, therefore, might be involved in the therapeutic actions of antidepressants [23]. Like other secreted proteins, BDNF arises from a precursor, proBDNF, which is proteolytically cleaved to produce mature BDNF [24,25]. With the discovery that proBDNF can have biological effects opposite to those of BDNF, through an action on a different receptor system [26], the proteolytic cleavage of proBDNF by the tPAplasminogen system may represent a mechanism by which the direction of BDNF/proBDNF action is controlled [27]. Thus, the tPA-plasminogen system may be implicated in MDD pathogenesis through the BDNF/proBDNF pathway. In addition to tPA, there is also evidence that other components related to tPA-plasminogen activity, such as plasminogen activator inhibitor-1 (PAI-1), could also be related to MDD pathogenesis. PAI-1 is the major inhibitor of tPA-plasminogen signaling [28] and there is evidence to support an association between PAI-1 and CVD pathogenesis [29,30]. Furthermore, PAI-1 is also a major stress-regulated gene [31]. Clinical study has demonstrated that women with MDD have higher PAI-1 levels than normal controls [32]. Similarly, in a male population, it was found that depressed subjects had higher levels of PAI-1 activity than non-depressed subjects [33]. In a recent study, it was found that negative life events were positively associated with plasma PAI-1 antigen concentrations in spousal dementia caregivers low in personal mastery [34]. Furthermore, our recent genetic study found that common genetic polymorphisms in the PAI-1 gene are associated with major depression, suggesting that PAI-1 genetic variants may play a role in major depression susceptibility [35]. From the above evidence, dysfunction in the tPA-plasmin pathway may be implicated in the link between MDD and CVD. This link may have implications for future research and treatment. First, genetic knockout or transgenic mice have been widely used for the study of CVD as well as MDD. Genetic manipulation of the tPA system could be used to test for co-morbidity of MDD and CVD. For example, PAI-1 levels in depressed or CVD subjects are higher than normal controls [29,32,33]. Transgenic mice overexpressing the gene encoding PAI-1 could be used to determine whether this elevation causes comorbid CVD and MDD. Secondly, the function of the tPA-plasminogen system is largely determined by genetic factors and genetic polymorphisms in components of the tPA system have been associated with CVD [36]. Recently, Scherrer et al. utilized a twin design to test whether there are common genetic and environmental risk factors underlying depression symptoms, hypertension and heart disease. They found the genetic correlations were significant between depression symptoms and hypertension, and between depression symptoms and heart disease, suggesting that the co-occurrence of MDD and CVD is partly explained by common genetic risk factors [37]. Candidates for molecular genetic studies (e.g., mutation analysis,
167
microarray, or genetic association studies) of CVD comorbid with MDD include genes that are related to the tPA-plasminogen system; such studies may help us to better understand the link between MDD and CVD. Finally, if tPA-plasminogen dysfunction is the link between CVD and MDD, agents that modulate tPA-plasminogen activity could be potential drugs for the treatment of patients with both CVD and MDD. For example, hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors, otherwise known as statins, are the treatment of choice for the management of hypercholesterolaemia and in vitro studies have demonstrated that statins can induce tPA and inhibit PAI-1 [38,39]. It is therefore possible that statins could act through the tPA-plasminogen pathway to usefully treat CVD patients comorbid with MDD. References [1] Anda R, Williamson D, Jones D, Macera C, Eaker E, Glassman A, et al. Depressed affect, hopelessness. And the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology 1993;4:285–94. [2] Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995;91:999–1005. [3] Wassertheil-Smoller S, Applegate WB, Berge K, Chang CJ, Davis BR, Grimm Jr R, et al. Change in depression as a precursor of cardiovascular events. SHEP cooperative research group (Systoloc Hypertension in the elderly). Arch Int Med 1996;156:553–61. [4] Penninx BW, Beekman AT, Honig A, Deeg DJ, Schoevers RA, van Eijk JT, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiat 2001;58:221–7. [5] Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med 2004;66:802–13. [6] Gonzalez MB, Snyderman TB, Colket JT, Arias RM, Jiang JW, O’Connor CM, et al. Depression in patients with coronary artery disease. Depression 1996;4:57–62. [7] Joynt KE, Whellan DJ, O’Connor CM. Depression and cardiovascular disease: mechanisms of interaction. Biol Psychiat 2003;54:248–61. [8] Shimbo D, Davidson KW, Haas DC, Fuster V, Badimon JJ. Negative impact of depression on outcomes in patients with coronary artery disease: mechanisms, treatment considerations, and future directions. J Thromb Haemost 2005;3:897–908. [9] Roberts RE, Kaplan GA, Shema SJ, Strawbridge WJ. Are the obese at greater risk for depression? Am J Epidemiol 2000;152:163–70. [10] Talbot F, Nouwen A. A review of the relationship between depression and diabetes in adults: is there a link? Diabetes Care 2000;23:1556–62. [11] Rutledge T, Hogan BE. A quantitative review of prospective evidence linking psychological factors with hypertension development. Psychosom Med 2002;64:758–66. [12] Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiat 1997;54:597–606. [13] Yepes M, Lawrence DA. Tissue-type plasminogen activator and neuroserpin: a well-balanced act in the nervous system? Trends Cardiovasc Med 2004;14:173–80. [14] Pearson TA, LaCava J, Weil HF. Epidemiology of thrombotic-hemostatic factors and their associations with cardiovascular disease. Am J Clin Nutr 1997;65(Suppl. 5):1674S–82S. [15] Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost 1999;82:259–70. [16] Lowe GD, Danesh J, Lewington S, Walker M, Lennon L, Thomson A, et al. Tissue plasminogen activator antigen and coronary heart disease. Prospective study and meta-analysis. Eur Heart J 2004;25:252–9. [17] Koenig W. Haemostatic risk factors for cardiovascular diseases. Eur Heart J 1998;19(Suppl. C):C39–43. [18] Sappino AP, Madani R, Huarte J, Belin D, Kiss JZ, Wohlwend A, et al. Extracellular proteolysis in the adult murine brain. J Clin Invest 1993;92:679–85. [19] Madani R, Nef S, Vassalli JD. Emotions are building up in the field of extracellular proteolysis. Trends Mol Med 2003;9:183–5. [20] Pawlak R, Magarinos AM, Melchor J, McEwen B, Strickland S. Tissue plasminogen activator in the amygdala is critical for stress-induced anxietylike behaviour. Nat Neurosci 2003;6:168–74. [21] Pietraszek MH, Takada Y, Nishimoto M, Ohara K, Ohara K, Takada A. Fibrinolytic activity in depression and neurosis. Thromb Res 1991;63:661–6. [22] Tsai SJ. The possible role of tissue-type plasminogen activator and the plasminogen system in the pathogenesis of major depression. Med Hypotheses 2006;66:319–22. [23] Duman RS. Synaptic plasticity and mood disorders. Mol Psychiat 2002;7(Suppl. 1):S29–34. [24] Seidah NG, Benjannet S, Pareek S, Chretien M, Murphy RA. Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett 1996;379:247–50.
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[25] Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 2004;306:487–91. [26] Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci 2005;25:5455–63. [27] Lu B, Pang PT, Woo NH. The yin and yang of neurotrophin action. Nat Rev Neurosci 2005;6:603–14. [28] Salles FJ, Strickland S. Localization and regulation of the tissue plasminogen activator-plasmin system in the hippocampus. J Neurosci 2002;22:2125–34. [29] Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985;313:1557–63. [30] Iacoviello L, Burzotta F, Di Castelnuovo A, Zito F, Marchioli R, Donati MB. The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial infarction: a meta-analysis. Thromb Haemost 1998;80:1029–30. [31] Yamamoto K, Takeshita K, Shimokawa T, Yi H, Isobe K, Loskutoff DJ, et al. Plasminogen activator inhibitor-1 is a major stress-regulated gene: implications for stress-induced thrombosis in aged individuals. Proc Natl Acad Sci USA 2002;99:890–5. [32] Eskandari F, Mistry S, Martinez PE, Torvik S, Kotila C, Sebring N, et al. Younger, premenopausal women with major depressive disorder have more abdominal fat and increased serum levels of prothrombotic factors: implications for greater cardiovascular risk. Metabolism 2005;54:918–24.
[33] Lahlou-Laforet K, Alhenc-Gelas M, Pornin M, Bydlowski S, Seigneur E, Benetos A, et al. Relation of depressive mood to plasminogen activator inhibitor, tissue plasminogen activator, and fibrinogen levels in patients with versus without coronary heart disease. Am J Cardiol 2006;97:1287–91. [34] Mausbach BT, von Känel R, Patterson TL, Dimsdale JE, Depp CA, Aschbacher K, et al. The moderating effect of personal mastery and the relations between stress and Plasminogen Activator Inhibitor-1 (PAI-1) antigen. Health Psychol 2008;27(Suppl. 2):S172–9. [35] Tsai SJ, Hong CJ, Liou YJ, Yu YWY, Chen TJ. Plasminogen activator inhibitor-1 gene is associated with major depression and antidepressant treatment response. Pharmacogenet Genomics 2008;18:869–75. [36] Voetsch B, Loscalzo J. Genetic determinants of arterial thrombosis. Arterioscler Thromb Vasc Biol 2004;24:216–29. [37] Scherrer JF, Xian H, Bucholz KK, Eisen SA, Lyons MJ, Goldberg J, et al. A twin study of depression symptoms, hypertension, and heart disease in middleaged men. Psychosom Med 2003;65:548–57. [38] Lopez S, Peiretti F, Bonardo B, Juhan-Vague I, Nalbone G. Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells. Atherosclerosis 2000;152:359–66. [39] Mussoni L, Banfi C, Sironi L, Arpaia M, Tremoli E. Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells. Thromb Haemost 2000;84:59–64.
Contents lists available at ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Is dysfunction of the tissue plasminogen activator (tPA)-plasmin pathway a link between major depression and cardiovascular disease? Sheue-Jane Hou a, Feng-Chang Yen a, Shih-Jen Tsai b,c,* a
Division of Psychiatry, Cheng-Hsin Rehabilitation and Medical Center, Taipei, Taiwan, ROC Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan, ROC c Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC b
a r t i c l e
i n f o
Article history: Received 25 June 2008 Accepted 10 September 2008
s u m m a r y Epidemiological, genetic and clinical studies have demonstrated an association between major depressive disorder (MDD) and cardiovascular disease (CVD). For example, MDD is a risk factor for the development of CVD, while around one fifth of patients with CVD have MDD and a significantly larger percentage have subsyndromal symptoms of depression. Furthermore, patients with CVD and depression have an increased risk of future cardiac events compared to similar cohorts without depression, independent of baseline cardiac dysfunction. Despite evidence that CVD and MDD are epidemiologically linked, the cause of this correlation is still unknown. Several risk factors including physical and psychological stress, smoking, physical inactivity and inflammation have been proposed to mediate the interaction between MDD and CVD. The tissue-type plasminogen activator (tPA)-plasminogen proteolytic cascade is widely expressed in the brain. Accumulating evidence from preclinical and clinical studies suggests that tPA and its inhibitor, plasminogen activator inhibitor-1, are related to stress reaction and depression. In addition, brain-derived neurotrophic factor (BDNF) is important for the pathogenesis of MDD and the tPAplasminogen proteolytic cascade has been implicated in the cleavage of proBDNF to BDNF in the brain, by which the direction of BDNF action is controlled. Thus, it is proposed that tPA-plasmin pathway dysfunction may play a role in the link between MDD and CVD. Future study of the components in the tPAplasminogen system in CVD patients comorbid with MDD may lead to new, potentially important insights into the link between MDD and CVD, and might also contribute to novel strategies for the management of these two common and devastating diseases. Ó 2008 Elsevier Ltd. All rights reserved.
Worldwide, major depressive disorder (MDD) and cardiovascular disease (CVD) are two of the most prevalent health problems and are leading cause of disability. There is a substantial body of evidence suggesting a strong relation between MDD and CVD. For example, both epidemiological and clinical studies have demonstrated that subjects initially free of CVD but with depression have a 2-fold to 4-fold increased risk of developing CVD independent of other known risk factors [1–3]. In addition, depression is also an independent predictor of poor outcome following a cardiac event [4,5]. In turn, CVD patients often develop MDD. Gonzalez et al. found MDD in 23% of patients with coronary artery disease [6]. Despite evidence that MDD and CVD are epidemiologically linked, the cause of this correlation is still unknown. Hypotheses regarding the link between MDD and CVD include physical and psychological stress, smoking, physical inactivity and dysregulation of inflammatory function [for review see Refs. [7,8]]. In addi-
* Corresponding author. Address: Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Shih-Pai Road, Sector 2, 11217, Taipei, Taiwan. Tel.: +886 2 28757027x276; fax: +886 2 28725643. E-mail address: [email protected] (S.-J. Tsai). 0306-9877/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2008.09.009
tion, other traditional CVD risk factors (including diabetes, obesity and hypertension) have also been associated with MDD [9–11]. Here, from studies of thrombolytic factors in MDD and the neurotropic model of MDD [12], we propose that dysfunction of the tissue plasminogen activator (tPA)-plasmin pathway could also link MDD and CVD. tPA is a highly specific serine proteinase that converts the plasminogen zymogen to the active serine protease plasmin. tPA is found in the blood, where its primary function is as a thrombolytic enzyme, and, in the brain, it promotes events associated with synaptic plasticity and cell death in a number of settings, such as neurodegeneration and seizures [13]. Since thrombosis is involved in the pathogenesis of CVD [14] and the tPA-plasmin proteolytic cascade is known to be important for thrombolysis [15], there is abundant evidence that the tPA-plasmin pathway is involved in the pathogenesis of CVD [for review see Ref. [16]]. Furthermore, decreased thrombolysis capacity has been identified prospectively as having an important role in the development of CVD [17]. Recently, an association between the tPA-plasmin proteolytic cascade and MDD has been demonstrated in clinical as well as animal studies. In the adult murine brain, components of the
S.-J. Hou et al. / Medical Hypotheses 72 (2009) 166–168
tPA-plasmin system are abundantly expressed in areas such as the hippocampus [18], a region important for the pathogenesis of MDD. Accumulating evidence regarding the expression and role of the tPA pathway also suggests that this pathway has a key role in the biology of emotions [for review see Ref. [19]]. Stress is a common precipitating factor for MDD and tPA is also critical for the stress reaction. In mice subjected to acute restraint stress, tPA activity was rapidly up-regulated in the amygdala, while mice in which the tPA gene had been disrupted did not show anxiety after repeated stress [20]. In a clinical study, patients with depression showed significantly lower plasma tPA concentrations than normal persons [21]. In addition to direct measures of tPA levels in depression, tPA has been hypothesised to be linked to MDD through its extracellular proteolysis function [22]. Briefly, evidence from animal and human studies has suggested that brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family known to regulate neuronal plasticity and survival, may play an important role in the pathogenesis of MDD and, therefore, might be involved in the therapeutic actions of antidepressants [23]. Like other secreted proteins, BDNF arises from a precursor, proBDNF, which is proteolytically cleaved to produce mature BDNF [24,25]. With the discovery that proBDNF can have biological effects opposite to those of BDNF, through an action on a different receptor system [26], the proteolytic cleavage of proBDNF by the tPAplasminogen system may represent a mechanism by which the direction of BDNF/proBDNF action is controlled [27]. Thus, the tPA-plasminogen system may be implicated in MDD pathogenesis through the BDNF/proBDNF pathway. In addition to tPA, there is also evidence that other components related to tPA-plasminogen activity, such as plasminogen activator inhibitor-1 (PAI-1), could also be related to MDD pathogenesis. PAI-1 is the major inhibitor of tPA-plasminogen signaling [28] and there is evidence to support an association between PAI-1 and CVD pathogenesis [29,30]. Furthermore, PAI-1 is also a major stress-regulated gene [31]. Clinical study has demonstrated that women with MDD have higher PAI-1 levels than normal controls [32]. Similarly, in a male population, it was found that depressed subjects had higher levels of PAI-1 activity than non-depressed subjects [33]. In a recent study, it was found that negative life events were positively associated with plasma PAI-1 antigen concentrations in spousal dementia caregivers low in personal mastery [34]. Furthermore, our recent genetic study found that common genetic polymorphisms in the PAI-1 gene are associated with major depression, suggesting that PAI-1 genetic variants may play a role in major depression susceptibility [35]. From the above evidence, dysfunction in the tPA-plasmin pathway may be implicated in the link between MDD and CVD. This link may have implications for future research and treatment. First, genetic knockout or transgenic mice have been widely used for the study of CVD as well as MDD. Genetic manipulation of the tPA system could be used to test for co-morbidity of MDD and CVD. For example, PAI-1 levels in depressed or CVD subjects are higher than normal controls [29,32,33]. Transgenic mice overexpressing the gene encoding PAI-1 could be used to determine whether this elevation causes comorbid CVD and MDD. Secondly, the function of the tPA-plasminogen system is largely determined by genetic factors and genetic polymorphisms in components of the tPA system have been associated with CVD [36]. Recently, Scherrer et al. utilized a twin design to test whether there are common genetic and environmental risk factors underlying depression symptoms, hypertension and heart disease. They found the genetic correlations were significant between depression symptoms and hypertension, and between depression symptoms and heart disease, suggesting that the co-occurrence of MDD and CVD is partly explained by common genetic risk factors [37]. Candidates for molecular genetic studies (e.g., mutation analysis,
167
microarray, or genetic association studies) of CVD comorbid with MDD include genes that are related to the tPA-plasminogen system; such studies may help us to better understand the link between MDD and CVD. Finally, if tPA-plasminogen dysfunction is the link between CVD and MDD, agents that modulate tPA-plasminogen activity could be potential drugs for the treatment of patients with both CVD and MDD. For example, hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors, otherwise known as statins, are the treatment of choice for the management of hypercholesterolaemia and in vitro studies have demonstrated that statins can induce tPA and inhibit PAI-1 [38,39]. It is therefore possible that statins could act through the tPA-plasminogen pathway to usefully treat CVD patients comorbid with MDD. References [1] Anda R, Williamson D, Jones D, Macera C, Eaker E, Glassman A, et al. Depressed affect, hopelessness. And the risk of ischemic heart disease in a cohort of U.S. adults. Epidemiology 1993;4:285–94. [2] Frasure-Smith N, Lesperance F, Talajic M. Depression and 18-month prognosis after myocardial infarction. Circulation 1995;91:999–1005. [3] Wassertheil-Smoller S, Applegate WB, Berge K, Chang CJ, Davis BR, Grimm Jr R, et al. Change in depression as a precursor of cardiovascular events. SHEP cooperative research group (Systoloc Hypertension in the elderly). Arch Int Med 1996;156:553–61. [4] Penninx BW, Beekman AT, Honig A, Deeg DJ, Schoevers RA, van Eijk JT, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiat 2001;58:221–7. [5] Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a meta-analysis. Psychosom Med 2004;66:802–13. [6] Gonzalez MB, Snyderman TB, Colket JT, Arias RM, Jiang JW, O’Connor CM, et al. Depression in patients with coronary artery disease. Depression 1996;4:57–62. [7] Joynt KE, Whellan DJ, O’Connor CM. Depression and cardiovascular disease: mechanisms of interaction. Biol Psychiat 2003;54:248–61. [8] Shimbo D, Davidson KW, Haas DC, Fuster V, Badimon JJ. Negative impact of depression on outcomes in patients with coronary artery disease: mechanisms, treatment considerations, and future directions. J Thromb Haemost 2005;3:897–908. [9] Roberts RE, Kaplan GA, Shema SJ, Strawbridge WJ. Are the obese at greater risk for depression? Am J Epidemiol 2000;152:163–70. [10] Talbot F, Nouwen A. A review of the relationship between depression and diabetes in adults: is there a link? Diabetes Care 2000;23:1556–62. [11] Rutledge T, Hogan BE. A quantitative review of prospective evidence linking psychological factors with hypertension development. Psychosom Med 2002;64:758–66. [12] Duman RS, Heninger GR, Nestler EJ. A molecular and cellular theory of depression. Arch Gen Psychiat 1997;54:597–606. [13] Yepes M, Lawrence DA. Tissue-type plasminogen activator and neuroserpin: a well-balanced act in the nervous system? Trends Cardiovasc Med 2004;14:173–80. [14] Pearson TA, LaCava J, Weil HF. Epidemiology of thrombotic-hemostatic factors and their associations with cardiovascular disease. Am J Clin Nutr 1997;65(Suppl. 5):1674S–82S. [15] Collen D. The plasminogen (fibrinolytic) system. Thromb Haemost 1999;82:259–70. [16] Lowe GD, Danesh J, Lewington S, Walker M, Lennon L, Thomson A, et al. Tissue plasminogen activator antigen and coronary heart disease. Prospective study and meta-analysis. Eur Heart J 2004;25:252–9. [17] Koenig W. Haemostatic risk factors for cardiovascular diseases. Eur Heart J 1998;19(Suppl. C):C39–43. [18] Sappino AP, Madani R, Huarte J, Belin D, Kiss JZ, Wohlwend A, et al. Extracellular proteolysis in the adult murine brain. J Clin Invest 1993;92:679–85. [19] Madani R, Nef S, Vassalli JD. Emotions are building up in the field of extracellular proteolysis. Trends Mol Med 2003;9:183–5. [20] Pawlak R, Magarinos AM, Melchor J, McEwen B, Strickland S. Tissue plasminogen activator in the amygdala is critical for stress-induced anxietylike behaviour. Nat Neurosci 2003;6:168–74. [21] Pietraszek MH, Takada Y, Nishimoto M, Ohara K, Ohara K, Takada A. Fibrinolytic activity in depression and neurosis. Thromb Res 1991;63:661–6. [22] Tsai SJ. The possible role of tissue-type plasminogen activator and the plasminogen system in the pathogenesis of major depression. Med Hypotheses 2006;66:319–22. [23] Duman RS. Synaptic plasticity and mood disorders. Mol Psychiat 2002;7(Suppl. 1):S29–34. [24] Seidah NG, Benjannet S, Pareek S, Chretien M, Murphy RA. Cellular processing of the neurotrophin precursors of NT3 and BDNF by the mammalian proprotein convertases. FEBS Lett 1996;379:247–50.
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