Role of Caspase 1 in Ischemia/Reperfusion Injury of the Myocardium

Abstract

Acute occlusion of a coronary artery can result in myocardial infarction-a leading cause of premature death. Prompt restoration of blood flow to the myocardium can prevent excessive death of cardiomyocytes and improve clinical outcome. Although the major mechanism of cell death after reperfusion is necrosis, it is now recognized that many other cell death pathways may be involved in ischemia-reperfusion (I/R) injury. Pyroptosis is one such cell death pathway that is caspase-1-dependent and induced in response to cellular insult. The activated caspase-1 protease cleaves and activates specific cellular targets including gasdermin D and the pro-inflammatory cytokines interleukin-1 and interleukin-18. The Nterminal fragment of gasdermin D forms plasma membrane pores resulting in cytosolic leakage and cell rupture, releasing interleukin-1beta and interleukin-18. Evidence suggests that inflammation induced by I/R via the pyroptotic pathway contributes to cardiomyocyte death, excessive scar formation and poor ventricular remodeling. For this reason, there is growing interest in targeting components of the pyroptotic pathway as a means of reducing I/R injury.

<p>Role of Caspase-1 in the Pathogenesis of Inflammatory-Associated Chronic Noncommunicable Diseases</p>

“…101,102 Conversely, it also reported that caspase-1 can directly initiate inflammatory-induced cell death through the activation of the gasdermin-D-induced pyroptosis pathway, which in turn results in cardiomyocyte death, excessive scar formation, and poor ventricular remodeling. 103 Other experimental studies on mice also reported that activation of NLRP3 inflammasome and caspase-1 may cause excessive cell death in cardiac ischemia. Thus, they suggested that inhibition of caspase-1 activation may have a great role in the progression of cardiac ischemia due to excessive cell death.…”

“…Surprisingly, in fibroblast cells, caspase-1 involves the maturation of IL-1β-mediated myofibroblast differentiation and collagen synthesis. 103,[116][117][118] In animals, fibroblasts are the most common cells of connective tissue that produce the structural framework of the tissue through the synthesis of extracellular matrix and collagen. Fibroblasts can also be involved in the inflammatory responses for tissue injuries or infections through the induction of chemokine synthesis.…”

Mitochondrial and mitochondrial‐independent pathways of myocardial cell death during ischaemia and reperfusion injury

“…Interaction of these proteins with cellular pattern recognition receptors can lead to the assembly of the intracellular NLRP3 inflammasome complex. The assembled NLRP3 inflammasome elicits auto‐proteolytic cleavage and activation of caspase‐1, which mediates the cleavage/maturation of the pro‐inflammatory cytokines, pro‐IL‐18 and pro‐IL‐1β, and cleaves/activates gasdermin‐D (GSDMD), releasing its N‐terminal fragment . Activated GSDMD‐N, as well as active caspase‐1, may induce the formation of membrane pores thus inducing cell lysis, called pyroptotic cell death .…”

Targeting myocardial ischaemic injury in the absence of reperfusion

“…In mice and rats with permanent coronary ligation, a marked increase in NLRP3, IL-1β, and IL-18 mRNA expression was found in the LV from 3 to 21 days after CAO, primarily located in myocardial fibroblasts [106]. Caspase-1 activity is increased in the myocardium minutes after the onset of ischaemia and remains elevated for several days, leading to cardiomyocyte death and amplification of inflammation [100]. Mice lacking caspase-1 that were subject to CAO exhibited both improved peri-infarct survival and a decreased rate of ventricular dilatation, presumably due in part to a decrease in MMP-3 activity, IL-18 production, and a reduction in the rate of apoptosis [34].…”