Therapeutic Potential of Gasdermin D-Mediated Myocardial Pyroptosis in Ischaemic Heart Disease: Expanding the Paradigm From Bench to Clinical Insights

Abstract

Ischaemic heart disease (IHD) remains a leading cause of global morbidity and mortality. One significant contributor to the pathology of IHD is the excessive release of inflammatory mediators during the disease progression. Pyroptosis is a form of programmed cell death (PCD) triggered by the activation of inflammasomes and caspase 1. The activation of inflammatory caspase 1 proteolytically cleaves gasdermin D (GSDMD) to the activated form amino acid terminus (GSDMD-NT), leading to disruption of the plasma membrane. This cascade of events is considered the canonical pathway of pyroptosis. IHD also caused oxidative stress, thereby triggering noncanonical pyroptosis via the activation of caspases 4/5/11. Previous studies have provided compelling evidence of the close relationship between pyroptosis and the aetiology of IHD (e.g., acute myocardial infarction, myocardial ischaemia and reperfusion injury and chronic myocardial infarction), as well as the association of pyroptosis with unfavourable clinical outcomes. Several interventions aimed at targeting pyroptosis have demonstrated promising therapeutic benefits against IHD-related pathologies. This review provides mechanistic insights into the roles of pyroptosis in IHD from in vitro, in vivo and clinical perspectives. In-depth understanding into this area could also pave the way for the future development of novel therapeutic strategies targeting pyroptosis in IHD.