- Email: [email protected]
Regulation of Ischemia-Induced Vascularization by Hypoxia-Inducible Factor 1
ABSTRACTS / Journal of Molecular and Cellular Cardiology 45 (2008) S1–S35
cantly altered cytokine expression and other inflammatory factors and suppressed cell proliferation. These treatments showed no adverse effects. Conclusions: We have revealed that several inflammatory factors are critical for the development of cardiovascular diseases. Specific regulation of these factors has the potential to provide novel and safe treatment. Keywords: Nuclear factor; Adhesion Molecule; Arteriosclerosis doi:10.1016/j.yjmcc.2008.09.610
S-C-6 Cardiac-specific autoantibodies as a therapeutic target for refractory heart failure due to dilated cardiomyopathy Tsutomu Yoshikawa1, Yuji Nagatomo1, Toshiaki Monkawa1, Satoshi Ogawa1, Akiyasu Baba2, Yasuhisa Wakabayashi2, Makoto Akaishi2 1 Keio University 2 Kitasato Institute Hospital Autoimmune disorder is one of the features characterizing dilated cardiomyopathy (DCM). Various anticardiac autoantibodies are found in approximately 85% of such patients. Among them, autoantibody directed against beta1-adrenergic receptors exerts agonist-like effect, inducing persistent myocardial damage as well as providing a substrate for fatal ventricular arrhythmias resulting in sudden cardiac death. Presence of autoantibody against M2muscarinic receptors is associated with atrial fibrillation. Presence of the autoantibody against Na-K-ATPase was the most powerful predictor of sudden death. Autoantibody directed against troponin I was found in PD1-/- mice, and was associated with increased L-type calcium current. Almost all of these pathophysiologically relevant autoantibodies belong to IgG3 subclass. We set out to remove such autoantibodies using immunoadsorption technique (IA) using highprofile tryptophan column, which had low antigenecity and high specificity for IgG subclass 3. IA therapy was conducted in 17 patients with DCM. Plasma brain natriuretic peptide levels were significantly decreased after completion of IA (p = 0.002). Six minutes walk distance was significantly increased (p = 0.01). Left ventricular ejection fraction tended to increase 3-6 months after completion of IA (p = 0.08). Conclusions: IA to remove cardiac-specific autoantibodies may become a promising therapeutic alternative in patients with refractory heart failure due to DCM. Keywords: dilated cardiomyopathy; autoantibody; immunoadsorption doi:10.1016/j.yjmcc.2008.09.611
S-D-1 Aldosterone Induced Vascular Inflammatory Disease: Mechanisms and Implications for Clinical Practice Ricardo Rocha MD Cardiovascular and Metabolism. Novartis Pharmaceuticals Corp, East Hanover, NJ A growing body of preclinical and clinical evidence has demonstrated that mineralocorticoids, especially aldosterone, are intimately involved in the development of target organ injury in all major target organs of hypertensive disease, and that pharmacological inhibition of mineralocorticoids, or adrenalectomy markedly reduces myocardial injury, stroke and renal vascular disease. Animal studies demonstrated that aldosterone/salt treatment induces inflammatory remodeling of coronary and renal arteries with associated ischemic and necrotic lesions. These mineralocorticoid/ salt-induced inflammatory changes are usually associated with
S7
activation of oxidative stress in vascular cells as well as the expression and progressive upregulation of proinflammatory mediators such as osteopontin, MCP-1, COX-2 and NF-kB. Importantly, the activation of proinflammatory mediators has been shown to be diminished and vascular and cardiac pathology reduced by aldosterone inhibition, implicating a role for these hormones in the progression of inflammatory injury in target tissues. In clinical studies, aldosterone antagonism has also been shown to provide significant end-organ protection in the heart and kidney. Indeed, this strategy has proven to be effective to improve endothelial dysfunction in hypertensive patients and to reduce cardiovascular morbidity and mortality in patients with congestive heart failure or left ventricular dysfunction following a myocardial infarction. Additional studies looking at the ability of aldosterone antagonism to reduce outcomes in other disease settings are currently ongoing. In addition, whether aldosterone synthesis inhibition can mimic the effect of mineralocorticoid receptor antagonism to attenuate end organ damage is currently under investigation. Thus, an increasing body of evidence now indicates that aldosterone antagonism may be a key therapeutic strategy for the treatment of hypertension and cardiovascular disease. doi:10.1016/j.yjmcc.2008.09.612
S-D-2 Regulation of Ischemia-Induced Vascularization by Hypoxia-Inducible Factor 1 Gregg L. Semenza The regulation of tissue perfusion is a major mechanism by which oxygen homeostasis is maintained. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional regulator that mediates adaptive responses to reduced pO2 in all metazoan species. HIF-1 is a heterodimer, consisting of a constitutively expressed HIF-1β subunit and an O2regulated HIF-1α subunit. In mammals, HIF-1 promotes angiogenesis, arteriogenesis, and vasculogenesis through the production of multiple angiogenic growth factors (including vascular endothelial growth factor and stromal-derived factor 1) in ischemic tissue and by cellautonomous effects on endothelial cells and bone marrow-derived angiogenic cells. Administration of AdCA5, an adenovirus that encodes a constitutively active form of the HIF-1α subunit, results in increased tissue perfusion in animal models of ischemic cardiovascular disease. Aging impairs ischemia-induced expression of HIF1α and multiple angiogenic cytokines, mobilization of angiogenic cells, maintenance of tissue viability, and recovery of limb perfusion following femoral artery ligation. administration of AdCA5 improves the recovery of perfusion in older mice to levels similar to those in young mice. Diabetes mellitus is also associated with a profound deficiency of circulating angiogenic cells and AdCA5 therapy increases the mobilization of circulating angiogenic cells and dramatically improves recovery of perfusion in db/db mice following femoral artery ligation. Thus, HIF-1α gene therapy overcomes the impairment of ischemia-induced angiogenesis caused by aging and diabetes, two of the most important factors contributing to critical limb ischemia. doi:10.1016/j.yjmcc.2008.09.613
S-D-3 Cold shock domain protein A, novel endogenous regulator of angiogenesis in heart Yukihiro Saito1, Hironori Nakagami2, Nobuyoshi Azuma1, Ryuichi Morishita3, Yasufumi Kaneda2, Tadahiro Sasajima1 1 Department of Surgery, Asahikawa Medical University 2 Division of Gene Therapy Science, Osaka University 3 Division of Clinical Gene Therapy, Osaka University
cantly altered cytokine expression and other inflammatory factors and suppressed cell proliferation. These treatments showed no adverse effects. Conclusions: We have revealed that several inflammatory factors are critical for the development of cardiovascular diseases. Specific regulation of these factors has the potential to provide novel and safe treatment. Keywords: Nuclear factor; Adhesion Molecule; Arteriosclerosis doi:10.1016/j.yjmcc.2008.09.610
S-C-6 Cardiac-specific autoantibodies as a therapeutic target for refractory heart failure due to dilated cardiomyopathy Tsutomu Yoshikawa1, Yuji Nagatomo1, Toshiaki Monkawa1, Satoshi Ogawa1, Akiyasu Baba2, Yasuhisa Wakabayashi2, Makoto Akaishi2 1 Keio University 2 Kitasato Institute Hospital Autoimmune disorder is one of the features characterizing dilated cardiomyopathy (DCM). Various anticardiac autoantibodies are found in approximately 85% of such patients. Among them, autoantibody directed against beta1-adrenergic receptors exerts agonist-like effect, inducing persistent myocardial damage as well as providing a substrate for fatal ventricular arrhythmias resulting in sudden cardiac death. Presence of autoantibody against M2muscarinic receptors is associated with atrial fibrillation. Presence of the autoantibody against Na-K-ATPase was the most powerful predictor of sudden death. Autoantibody directed against troponin I was found in PD1-/- mice, and was associated with increased L-type calcium current. Almost all of these pathophysiologically relevant autoantibodies belong to IgG3 subclass. We set out to remove such autoantibodies using immunoadsorption technique (IA) using highprofile tryptophan column, which had low antigenecity and high specificity for IgG subclass 3. IA therapy was conducted in 17 patients with DCM. Plasma brain natriuretic peptide levels were significantly decreased after completion of IA (p = 0.002). Six minutes walk distance was significantly increased (p = 0.01). Left ventricular ejection fraction tended to increase 3-6 months after completion of IA (p = 0.08). Conclusions: IA to remove cardiac-specific autoantibodies may become a promising therapeutic alternative in patients with refractory heart failure due to DCM. Keywords: dilated cardiomyopathy; autoantibody; immunoadsorption doi:10.1016/j.yjmcc.2008.09.611
S-D-1 Aldosterone Induced Vascular Inflammatory Disease: Mechanisms and Implications for Clinical Practice Ricardo Rocha MD Cardiovascular and Metabolism. Novartis Pharmaceuticals Corp, East Hanover, NJ A growing body of preclinical and clinical evidence has demonstrated that mineralocorticoids, especially aldosterone, are intimately involved in the development of target organ injury in all major target organs of hypertensive disease, and that pharmacological inhibition of mineralocorticoids, or adrenalectomy markedly reduces myocardial injury, stroke and renal vascular disease. Animal studies demonstrated that aldosterone/salt treatment induces inflammatory remodeling of coronary and renal arteries with associated ischemic and necrotic lesions. These mineralocorticoid/ salt-induced inflammatory changes are usually associated with
S7
activation of oxidative stress in vascular cells as well as the expression and progressive upregulation of proinflammatory mediators such as osteopontin, MCP-1, COX-2 and NF-kB. Importantly, the activation of proinflammatory mediators has been shown to be diminished and vascular and cardiac pathology reduced by aldosterone inhibition, implicating a role for these hormones in the progression of inflammatory injury in target tissues. In clinical studies, aldosterone antagonism has also been shown to provide significant end-organ protection in the heart and kidney. Indeed, this strategy has proven to be effective to improve endothelial dysfunction in hypertensive patients and to reduce cardiovascular morbidity and mortality in patients with congestive heart failure or left ventricular dysfunction following a myocardial infarction. Additional studies looking at the ability of aldosterone antagonism to reduce outcomes in other disease settings are currently ongoing. In addition, whether aldosterone synthesis inhibition can mimic the effect of mineralocorticoid receptor antagonism to attenuate end organ damage is currently under investigation. Thus, an increasing body of evidence now indicates that aldosterone antagonism may be a key therapeutic strategy for the treatment of hypertension and cardiovascular disease. doi:10.1016/j.yjmcc.2008.09.612
S-D-2 Regulation of Ischemia-Induced Vascularization by Hypoxia-Inducible Factor 1 Gregg L. Semenza The regulation of tissue perfusion is a major mechanism by which oxygen homeostasis is maintained. Hypoxia-inducible factor 1 (HIF-1) is a transcriptional regulator that mediates adaptive responses to reduced pO2 in all metazoan species. HIF-1 is a heterodimer, consisting of a constitutively expressed HIF-1β subunit and an O2regulated HIF-1α subunit. In mammals, HIF-1 promotes angiogenesis, arteriogenesis, and vasculogenesis through the production of multiple angiogenic growth factors (including vascular endothelial growth factor and stromal-derived factor 1) in ischemic tissue and by cellautonomous effects on endothelial cells and bone marrow-derived angiogenic cells. Administration of AdCA5, an adenovirus that encodes a constitutively active form of the HIF-1α subunit, results in increased tissue perfusion in animal models of ischemic cardiovascular disease. Aging impairs ischemia-induced expression of HIF1α and multiple angiogenic cytokines, mobilization of angiogenic cells, maintenance of tissue viability, and recovery of limb perfusion following femoral artery ligation. administration of AdCA5 improves the recovery of perfusion in older mice to levels similar to those in young mice. Diabetes mellitus is also associated with a profound deficiency of circulating angiogenic cells and AdCA5 therapy increases the mobilization of circulating angiogenic cells and dramatically improves recovery of perfusion in db/db mice following femoral artery ligation. Thus, HIF-1α gene therapy overcomes the impairment of ischemia-induced angiogenesis caused by aging and diabetes, two of the most important factors contributing to critical limb ischemia. doi:10.1016/j.yjmcc.2008.09.613
S-D-3 Cold shock domain protein A, novel endogenous regulator of angiogenesis in heart Yukihiro Saito1, Hironori Nakagami2, Nobuyoshi Azuma1, Ryuichi Morishita3, Yasufumi Kaneda2, Tadahiro Sasajima1 1 Department of Surgery, Asahikawa Medical University 2 Division of Gene Therapy Science, Osaka University 3 Division of Clinical Gene Therapy, Osaka University