The late phase of preconditioning and its natural clinical application—gene therapy

Abstract

There is little doubt that the discovery of ischemic preconditioning (PC) has been one of the fundamental milestones in the field of ischemic biology in the past 20 years. The purpose of this article is to review the pathophysiology and molecular basis of the late phase of myocardial PC. The exploitation of late PC for the development of novel gene therapy strategies aimed at inducing a permanently preconditioned cardiac phenotype (prophylactic cardioprotection) will also be discussed. Deciphering the mechanism of late PC has not only conceptual interest but also a considerable therapeutic implications, since transfer of the genes that underlie late PC would be expected to replicate the salubrious effects of this response of the heart to stress.

Preemptive conditioning of the swine heart by H11 kinase/Hsp22 provides cardiac protection through inducible nitric oxide synthase

“…5A, iNOS expression increased by an average of 2.5-fold in the myocardium injected with the Hsp22 adenovirus compared with the remote area, whereas it was unaffected by the LacZ adenovirus. Importantly, such increase of iNOS upon overexpression of Hsp22, albeit of limited amplitude, is quantitatively comparable to the upregulation found in different models of SWOP (6). There was a significant correlation between the overexpression level of Hsp22 and the increased expression of iNOS when individual data collected from four different hearts were plotted (Fig.…”

“…Despite the progress in stem cell research, the only alternative approach to restore impaired cardiac function due to MI to date is cardiac transplantation, which is severely limited by donor availability. A promising concept is preemptive conditioning of the heart (32) [or prophylactic cardioprotection (6)], in which the activation of prosurvival pathways in patients at risk of future heart attack might prevent cell death if an episode of potentially lethal ischemia occurs. In this study, we tested the hypothesis that H11 kinase/Hsp22 (Hsp22) represents a candidate for such an approach.…”

Cardioprotection Techniques: Preconditioning, Postconditioning and Remote Con-ditioning (Basic Science)

“…Similar findings have been reported with Ec-SOD adenoviral transfection [249,250]. The same authors are exploring the possibility of adenoviral transfection of other known distal mediators (such as COX-2) of delayed cardioprotection as a strategy for long-term 'prophylactic cardioprotection' in animal models (reviewed in [251]). The possibility of maintaining the heart in a state of cardioprotection is particularly attractive given the unpredictable onset of acute coronary syndromes.…”

Cardiac Postconditioning: An Additional Therapy to Limit Cell Death Following Myocardial Infarction

“…Classic IPC exerts its protective effects via the modification of existing proteins. In contrast, delayed preconditioning allows for the de novo synthesis of cytoprotective proteins (Bolli et al 2007). Another distinction between the two phases is that although classic IPC limits infarct size, it does not protect against postischemic myocardial contractile dysfunction or stunning.…”

“…Another distinction between the two phases is that although classic IPC limits infarct size, it does not protect against postischemic myocardial contractile dysfunction or stunning. Conversely, late IPC reduces myocardial cell death and preserves left ventricular function (Bolli et al 2007). These disparities suggest that late IPC would provide greater clinical benefits in terms of greater and longer lasting protection.…”