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.

Role of Pyroptosis in Diabetes and Its Therapeutic Implications

“…103 Growing evidence reports that DCM is closely related to pyroptosis associated with inflammation. 104,105 Pyroptosis-regulated cell death plays a significant role in DCM development. Previous research has documented that pyroptosis-related proteins, including GSDMD, caspase-1, NLRP3 inflammasome, and IL-1β expression levels are augmented in cardiac tissues.…”

Ferroptosis Is a Potential Novel Diagnostic and Therapeutic Target for Patients With Cardiomyopathy

“…Oxidative stress, which can interfere the balance between antioxidant capacity and the production of ROS, has been widely accepted as a common mechanism of DCM ( Khullar et al, 2010 ; Huynh et al, 2014 ). Considering that ROS formation promotes ferroptosis, it is very likely that ferroptosis is involved in DCM ( Anandhan et al, 2020 ; Chen et al, 2020 ). Zang et al (2020) showed that diabetes was capable of inducing autophagy deficiency with time, resulting in Nuclear factor-erythroid factor 2-related factor 2 (Nrf2)-mediated defense was turned off.…”

“…( Guiney et al, 2017 ; Stockwell et al, 2017 ). Recently, several studies have demonstrated that ferroptosis played a crucial role in myocardial homeostasis and pathology ( Akazawa, 2015 ; Conrad and Proneth, 2019 ; Chen et al, 2020 ; Li W. et al, 2020 ). However, the biological roles and regulation pathways of ferroptosis in cardiovascular diseases have not been entirely understood.…”

Programmed Cell Death. Review and Its Impact in Covid-19

“…The circadian rhythm is an endogenous mechanism that controls various cellular processes such as iron metabolism, oxidative stress, and cell death [53]. It is obvious that several mechanisms can act together in the same pathology or process and, also, the opposite, that several pathologies share the same mechanism [54][55][56][57]. Immunogenic cell death (ICD) is a functionally peculiar form of RCD that is sufficient to activate an adaptive immune response specific for endogenous (cellular) or exogenous (viral) antigens expressed by dying cells.…”