Distinct Types of Cell Death and the Implication in Diabetic Cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is a chronic complication of diabetes mellitus, characterized by abnormalities of myocardial structure and function. Researches on the models of type 1 and type 2 diabetes mellitus as well as the application of genetic engineering technology help in understanding the molecular mechanism of DCM. DCM has multiple hallmarks, including hyperglycemia, insulin resistance, increased free radical production, lipid peroxidation, mitochondrial dysfunction, endothelial dysfunction, and cell death. Essentially, cell death is considered to be the terminal pathway of cardiomyocytes during DCM. Morphologically, cell death can be classified into four different forms: apoptosis, autophagy, necrosis, and entosis. Apoptosis, as type I cell death, is the fastest form of cell death and mainly occurs depending on the caspase proteolytic cascade. Autophagy, as type II cell death, is a degradation process to remove damaged proteins, dysfunctional organelles and commences by the formation of autophagosome. Necrosis is type III cell death, which contains a great diversity of cell death processes, such as necroptosis and pyroptosis. Entosis is type IV cell death, displaying "cell-in-cell" cytological features and requires the engulfing cells to execute. There are also some other types of cell death such as ferroptosis, parthanatos, netotic cell death, lysosomal dependent cell death, alkaliptosis or oxeiptosis, which are possibly involved in DCM. Drugs or compounds targeting the signals involved in cell death have been used in clinics or experiments to treat DCM. This review briefly summarizes the mechanisms and implications of cell death in DCM, which is beneficial to improve the understanding of cell death in DCM and may propose novel and ideal strategies in future.

Keywords: apoptosis; autophagy; cell death; diabetic cardiomyopathy; entosis; necrosis.

Figure 1

Classification of cell death. Morphologically, cell death is classified into four different forms: type I or apoptosis, type II or autophagy, type III or necrosis, and type IV or entosis.

Figure 2

Mechanism of apoptosis in DCM. Both extrinsic apoptotic pathway and intrinsic apoptotic pathway are involved in DCM. Extrinsic pathway: long-term hyperglycemia triggers TNF-α to bind to TNF-α receptor (TNFR), initiates caspase 8 and subsequent caspase 3 activation, and finally results in apoptosis in the cardiomyocytes. Intrinsic pathway: Cyto C released into the cytosol combines with Apaf-1 to form a complex serving as a platform for caspase 9 and caspase 3 activation. Apoptosis induces cardiomyocyte cell loss to ultimately promote DCM.

Figure 3

Mechanism of necroptosis in DCM. Once recruited by RIP1 after HG exposure, RIP3 is activated by auto-phosphorylation to promote the recruitment and activation of mixed lineage kinase domain like protein (MLKL). RIP3 also phosphorylates CaMKII to induce mPTP opening. High glucose also increases ROS to activate CaMKII by oxidation and finally triggers mPTP opening, which is a final pathway of necroptosis during DCM.

Figure 4

Mechanism of pyroptosis in DCM. High glucose augments expression of NLRP3 and HuR to activate IL-1β or caspase 1/GSDMD-mediated pyroptosis. High glucose also elevates ROS production to increase AIM2 expression and ultimately mediates pyroptosis through caspase 1/GSDMD pathway.