Inhibition of Myocardial Apoptosis as a Therapeutic Target in Cardiovascular Disease Prevention

Abstract

Apoptosis is a type of programmed cell death that is evident during embryonic development and normal tissue turnover. When the apoptotic activity extends beyond physiologic limits, it can determine and/or contribute to those pathologic states characterized by excessive cell loss and impairment of organ function. The clinical development of caspase inhibitors may represent a potential therapeutic strategy for influencing the onset and progression of ventricular dysfunction to terminal failure. This article focuses on the caspase cascade, a fundamental enzymatic system for apoptotic cell death. Caspases do not constitute the death signals, but are implicated in their transmission. These cytoplasmic cysteine proteases have a dual role in apoptosis. Caspases can operate as initiators, activating an endonuclease that catalyzes deoxyribonucleic acid fragmentation. Alternatively, caspases can act as effectors, participating in the total disassembly of cell structures. For example, apoptosis represents the principal form of myocyte death in the region of an acute myocardial infarction. In addition, apoptosis in the region bordering the infarct can influence the development of ischemic cardiomyopathy and ventricular dilation.

Novel Cardioprotective Role of a Small Heat-Shock Protein, Hsp20, Against Ischemia/Reperfusion Injury

“…It has been shown that caspase-3 expression is increased in association with heart failure and apoptosis in experimental animals. 34 Several groups have reported that direct blockade of caspase activation with a peptide inhibitor protects the myocardium against lethal reperfusion injury. 34,35 In contrast, hearttargeted overexpression of caspase-3 in mice has been shown to increase infarct size and depress cardiac function.…”

Anti-Apoptotic Effects of Caspase Inhibitors on Rat Intervertebral Disc Cells

“…poptosis, or programmed cell death, is mediated by the activation of caspases (cysteine-containing aspartatespecific proteases, a group of proteolytic enzymes) and is thought to be a critical component of acute and chronic diseases such as myocardial infarction, stroke, neurodegenerative diseases, and disc degeneration [1][2][3] . There are several caspases, and they act as either initiators (caspase-2, 8, and 9) or executioners (caspase-3, 6, and 7) of apoptosis 4,5 .…”

“…Pancaspase inhibition more effectively decreased apoptosis than did caspase-8 inhibition. The use of caspase inhibitors has been reported to prevent or attenuate cell death associated with ischemic injury in the brain and heart and to protect against hepatic toxicity 1,[8][9][10][11][12][13] . Our results suggest that pancaspase inhibitors might offer a therapeutic benefit in the treatment of disc degeneration.…”

Pharmacoinvasive Therapy

“…Continued investigation into pharmacological and catheterbased interventions that preserve myocardial function is needed to amplify the benefits of a pharmacoinvasive strategy. [81][82][83][84] Figure 3. Proposal for pharmacoinvasive reperfusion of patients with STEMI in the future.…”