Diabetic cardiomyopathy: Importance of direct evidence to support the roles of NOD-like receptor protein 3 inflammasome and pyroptosis

Abstract

Recently, the roles of pyroptosis, a form of cell death induced by activated NOD-like receptor protein 3 (NLRP3) inflammasome, in the pathogenesis of diabetic cardiomyopathy (DCM) have been extensively investigated. However, most studies have focused mainly on whether diabetes increases the NLRP3 inflammasome and associated pyroptosis in the heart of type 1 or type 2 diabetic rodent models, and whether various medications and natural products prevent the development of DCM, associated with decreased levels of cardiac NLRP3 inflammasome and pyroptosis. The direct link of NLRP3 inflammasome and associated pyroptosis to the pathogenesis of DCM remains unclear based on the limited evidence derived from the available studies, with the approaches of NLRP3 gene silencing or pharmaceutical application of NLRP3 specific inhibitors. We thus emphasize the requirement for more systematic studies that are designed to provide direct evidence to support the link, given that several studies have provided both direct and indirect evidence under specific conditions. This editorial emphasizes that the current investigation should be circumspect in its conclusion, i.e., not overemphasizing its role in the pathogenesis of DCM with the fact of only significantly increased expression or activation of NLRP3 inflammasome and pyroptosis in the heart of diabetic rodent models. Only clear-cut evidence-based causative roles of NLRP3 inflammasome and pyroptosis in the pathogenesis of DCM can help to develop effective and safe medications for the clinical management of DCM, targeting these biomarkers.

Keywords: Diabetic cardiomyopathy; Nucleotide oligomerization domain; NOD-like receptor protein 3 inflammasome; Cardiac cell death; Pyroptosis

Core Tip: The involvement of the NOD-like receptor protein 3 (NLRP3) inflammasome and pyroptosis in the pathogenesis of diabetic cardiomyopathy (DCM) has been extensively explored. However, most studies focused on whether diabetes causes NLRP3 inflammasome activation and pyroptosis in the diabetic heart, as well as the potential of medications and natural products to mitigate DCM progression along with reducing NLRP3 inflammasome expression and pyroptosis. Few studies directly investigated the roles of NLRP3 inflammasome and pyroptosis in the development of DCM, utilizing appropriate approaches, such as NLRP3 gene silencing or pharmaceutical NLRP3 inhibitors. Therefore, this aspect of investigation is an urgent need, as stated in this editorial.