Growth Hormone Releasing Hormone (GHRH) Agonist Improves Cardiac Performance in the Chronic Model of Myocardial Infarction (MI) in Rats

Abstract

Cardiomyopathy in the setting of coronary artery disease (ischemic cardiomyopathy) is the major cause of heart failure in the developed world and a significant cause of morbidity and mortality. The degree of left ventricular dysfunction in this setting is often out of proportion to the amount of overtly infarcted tissue. Moreover, how decreased delivery of oxygen and nutrients leads to impaired contractility remains incompletely understood. The PHD prolyl hydroxylases are oxygen-sensitive enzymes that transduce changes in oxygen availability into changes in the stability and activity of the HIF transcription factor, a master regulator of genes that promote survival in a low oxygen-environment. We found that cardiac-specific PHD inactivation in mice causes ultrastructural, histological, and functional changes reminiscent of ischemic cardiomyopathy over time. Moreover, chronic expression of a stabilized HIFa variant in cardiomyocytes also led to dilated cardiomyopathy. In addition, we show that HIFa is upregulated in a murine model for ischemic cardiomyopathy, as well as samples of patients with chronic ischemia and cardiomyopathy. Together, our data establish that chronic PHD inactivation, and consequent HIF activation, plays a causal role in the pathogenesis of ischemic cardiomyopathy.