Mechanisms of load dependency of myocardial ischemia reperfusion injury

Abstract

Coronary artery disease and associated ischemic heart disease are prevalent disorders worldwide. Further, systemic hypertension is common and markedly increases the risk for heart disease. A common denominator of systemic hypertension of various etiologies is increased myocardial load/mechanical stress. Thus, it is likely that high pressure/mechanical stress attenuates the contribution of cardioprotective but accentuates the contribution of cardiotoxic pathways thereby exacerbating the outcome of an ischemia reperfusion insult to the heart. Critical events which contribute to cardiomyocyte injury in the ischemic-reperfused heart include cellular calcium overload and generation of reactive oxygen/nitrogen species which, in turn, promote the opening of the mitochondrial permeability transition pore, an important event in cell death. Increasing evidence also indicates that the myocardium is capable of mounting a robust inflammatory response which contributes importantly to tissue injury. On the other hand, cardioprotective maneuvers of ischemic preconditioning and postconditioning have led to identification of complex web of signaling pathways (e.g., reperfusion injury salvage kinase) which ultimately converge on the mitochondria to exert cytoprotection. The present review is intended to briefly describe mechanisms of cardiac ischemia reperfusion injury followed by a discussion of our work focused on how pressure/mechanical stress modulates endogenous cardiotoxic and cardioprotective mechanisms to ultimately exacerbate ischemia reperfusion injury.

Keywords: Heart; calcium overload; inflammation; ischemia-reperfusion; oxidative/nitrosative stress; pressure; signaling mechanisms; stem cells.

Figure 1

Diagram depicts critical events in cardiac ischemia reperfusion injury [27].

Figure 2

Diagram shows that cardioprotection of ischemic preconditioning (e.g. 3 bouts of ischemia (I) and reperfusion (R), each for 5 min, before a prolonged ischemia phase) and postconditioning (e.g., 6 cycles of I and R, each for 30 sec, at reperfusion) is associated with activation of the reperfusion injury salvage kinase (RISK) pathway. An important outcome relates to upregulation of phosphatidylinositol-3 kinase (PI3K)/Akt pathway which, in turn, leads to phosphorylation and inactivation of glycogen synthase kinase-3β (GSK-3β) culminating in inhibition of the mitochondrial permeability transition (MPT) pore. Also, shown is mitochondrial (mito.) K_ATP channels whose activation confers cardioprotection, likely through inhibition of MPT pore induction.

Figure 3

Diagram summarizes our working hypothesis that pressure overload accentuates cardiotoxic but attenuates cardioprotective mechanisms thereby causing exacerbation of myocardial ischemia-reperfusion injury.

Figure 4

Panel shows a dot matrix from flow cytometry-based assessment of cardiac cells from ischemic-reperfused hearts that co-express IL-17 and IL-23 (upper right quadrant; indicated by asterisk).

Figure 5

Scatter plots depict early apoptotic (green), late apoptotic (blue) and necrotic (red) cell death in cardiac cell preparations of ischemic-reperfused hearts that were subjected to either 80 or 160 cmH₂O. Immediately before the ischemic phase, hearts were transplanted (through the coronary arteries) with Sca1⁺ cells.

Figure 6

Schematic diagram showing major relevant pathways involved in the effect of pressure overload on the ischemic reperfused heart. An ischemia reperfusion insult exerts multiple and diverse effects including a) increased oxidative/nitrosative stress, b) intracellular calcium overload, c) downregulation of cardioprotection of PI3K-Akt/GSK-3β pathway and d) enhanced inflammatory responses, in part, through a GSK-3β-dependent mechanism involving increased GADD153 expression. Consequently, dysregulation of mitochondrial membrane potential leads to induction of the MPT pore. These changes are augmented by pressure overload, culminating in exacerbation of cell death/infarct size.