Program of Cell Survival Underlying Human and Experimental Hibernating Myocardium

Abstract

Abstract-Hibernating myocardium refers to chronically dysfunctional myocardium in patients with coronary artery disease in which cardiac viability is maintained and whose function improves after coronary revascularization. It is our hypothesis that long-term adaptive genomic mechanisms subtend the survival capacity of this ischemic myocardium. Therefore, the goal of this study was to determine whether chronic repetitive ischemia elicits a gene program of survival protecting hibernating myocardium against cell death. Accordingly, we measured the expression of survival genes in hibernating myocardium, both in patients surgically treated for hibernation and in a chronic swine model of repetitive ischemia reproducing the features of hibernation. Human hibernating myocardium was characterized by an upregulation of genes and corresponding proteins involved in anti-apoptosis (IAP), growth (VEGF, H11 kinase), and cytoprotection (HSP70, HIF-1␣, GLUT1). In the swine model, the same genes and proteins were upregulated after repetitive ischemia, which was accompanied by a concomitant decrease in myocyte apoptosis. These changes characterize viable tissue, because they were not found in irreversibly injured myocardium. Our report demonstrates a novel mechanism by which the activation of an endogenous gene program of cell survival underlies the sustained viability of the hibernating heart. Potentially, promoting such a program offers a novel opportunity to salvage postmitotic tissues in conditions of ischemia. Key Words: gene expression Ⅲ coronary artery disease Ⅲ ischemia Ⅲ stunning Ⅲ hibernation B ecause the cardiac myocyte has a limited capacity for regeneration, most forms of heart disease, including ischemic heart disease and heart failure, are characterized by a loss of cardiomyocytes. 1-3 Historically, any evidence of prolonged left ventricular dysfunction after myocardial ischemia was thought to be caused by irreversible myocyte damage. This traditional concept was challenged with the discoveries of myocardial stunning (in which ischemia is followed by prolonged but fully reversible dysfunction), 4 ischemic preconditioning (in which a brief ischemic episode protects the myocardium against a subsequent episode of sustained ischemia), 5 and hibernating myocardium (in which chronic dysfunction resulting from repeated ischemia recedes after bypass revascularization). 6,7 Hibernating myocardium is submitted to repetitive bouts of ischemia caused by normally occurring increases in myocardial metabolic demand in the face of significant coronary stenosis and limited coronary reserve, yet it does not develop irreversible damage. 8,9 The diagnosis of this condition is of the highest priority in patients with chronic coronary artery disease, because successful coronary revascularization and restoration of coronary flow reserve in hibernating myocardium are followed by an improvement of contractile performance; 10,11 however, if left untreated, this condition leads to progressive exacerbation of heart failure and death.Despite t...

Cardiac H11 kinase/Hsp22 stimulates oxidative phosphorylation and modulates mitochondrial reactive oxygen species production: Involvement of a nitric oxide-dependent mechanism

“…Hsp22 transcript and protein expression is up-regulated in different models of ischemia, both in swine and patients [3,4]. These data support the hypothesis that Hsp22 may promote cell survival in a context of acute, repetitive and chronic ischemia.…”

“…All animal procedures used in this study were in strict accordance with the European Community Council Directive (86-609/87-848 EEC) and recommendations of the French Ministère de l'Agriculture. 4 …”

Activation of the Bone Morphogenetic Protein Receptor by H11Kinase/Hsp22 Promotes Cardiac Cell Growth and Survival

“…27 The interaction of H11K with the BMP pathway explains the paradox that H11K is cytoprotective at low expression levels in vivo, and proapoptotic at supraphysiological concentration (or "overload") in vitro. 6 The cytoprotective effects, mediated by the PI3K/Akt pathway, are observed when H11K protein expression increases by 3-to 5-fold, which is found in vivo across species, such as dog, swine and humans, in both conditions of myocardial growth 2 and ischemia, 4 and in our TG model. 2,5 Reciprocally, proapoptotic effects occur in cell culture 17 through the activation of p38 MAPK when H11K is excessively overloaded.…”

“…1 An increase in H11K expression was found in a canine model of left ventricular hypertrophy, 2 in swine models of acute and repetitive myocardial ischemia, 3,4 and in patients with ischemic heart disease. 4 We generated a transgenic (TG) mouse with cardiac-specific overexpression of H11K to a level (3-to 5-fold) reproducing the increased expression found in the animal models and in patients. This TG model shows that H11K stimulates cardiac cell growth 2 and promotes cardiac cell survival to an extent reproducing the protection conferred by ischemic preconditioning.…”

Association of Plasma Concentration of Small Heat Shock Protein B7 With Acute Coronary Syndrome

“…4- 6 The general HSPs, including HSP60, 70 or 90, are associated with cardiovascular diseases including cardiac hypertrophy, 7,8 heart failure 9-12 and ischemia/reperfusion injury. 13- 16 Therefore, general HSPs may contribute to the protective mechanism during the pathogenesis of cardiac hypertrophy, heart failure, and ischemia/reperfusion injury. The involvement of sHSPs in cardiovascular diseases, however, remains largely unknown.…”