Early cardiac myocyte responses to hypoxia, ischemia, and reoxygenation.

Abstract

Myocardial ischemia is the most prevalent cause of morbidity and mortality in Western populations. The multiple ischemia-associated conditions share the common property of reduced, abnormal, or lost contraction due to impaired oxygen. delivery to a region of the myocardium. In all conditions the imbalance between oxygen supply and demand may be transitory, related to periods of physical exertion and/or mental stress. As a consequence, tissue experiencing repetitive ischemic episodes will suffer damage both from the ischemia (hypoxia, lactic acid), and from subsequent reperfusion (oxidative stress). Myocardial ischemia is commonly accompanied by hypertrophy involving increased cardiac growth and altered gene expression. By increasing left ventricle wall thickness and oxygen diffusion distances, hypertrophy exacerbates the ischemia and leads to a progressive and self-perpetuating pathology. In studies using models of simulated ischemia we have begun to unravel the molecular events that determine the responses of cardiac myocytes to redox stress. This work identified a unique network of intracellular signals, initiated by hypoxic and hyperoxic stresses, that promotes either adptive/defensive modifications, or cell death through apoptosis. Early signaling events in response to severe hypoxia include changes in lipid metabolism, calcium handling, intracellular pH, and protein kinase C activity. These culminate in the induction of immediate-early stress response genes including c-fos and cjun which code for transcription facto API. Downstream targets for the early responses include skeletal a-actin, atrial natriuretic peptide, and glycolytic enzyme genes. Chronic hypoxia involves down regulation of cAMP, protein kinase A, and enhanced apoptosis. Reoxygenation caused a weak transient activation of mitogen activated protein kinase, strong sustained activation of the stress activated protein kinase cascade, induction of downstream targets including API, suppression of Spl activity, and an additional wave of apoptosis.