Cellular interplay between cardiomyocytes and non-myocytes in diabetic cardiomyopathy

Abstract

Patients with Type 2 diabetes mellitus (T2DM) frequently exhibit a distinctive cardiac phenotype known as diabetic cardiomyopathy. Cardiac complications associated with T2DM include cardiac inflammation, hypertrophy, fibrosis and diastolic dysfunction in the early stages of the disease, which can progress to systolic dysfunction and heart failure. Effective therapeutic options for diabetic cardiomyopathy are limited and often have conflicting results. The lack of effective treatments for diabetic cardiomyopathy is due in part, to our poor understanding of the disease development and progression, as well as a lack of robust and valid preclinical human models that can accurately recapitulate the pathophysiology of the human heart. In addition to cardiomyocytes, the heart contains a heterogeneous population of non-myocytes including fibroblasts, vascular cells, autonomic neurons and immune cells. These cardiac non-myocytes play important roles in cardiac homeostasis and disease, yet the effect of hyperglycaemia and hyperlipidaemia on these cell types are often overlooked in preclinical models of diabetic cardiomyopathy. The advent of human induced pluripotent stem cells provides a new paradigm in which to model diabetic cardiomyopathy as they can be differentiated into all cell types in the human heart. This review will discuss the roles of cardiac non-myocytes and their dynamic intercellular interactions in the pathogenesis of diabetic cardiomyopathy. We will also discuss the use of sodium-glucose cotransporter 2 inhibitors as a therapy for diabetic cardiomyopathy and their known impacts on non-myocytes. These developments will no doubt facilitate the discovery of novel treatment targets for preventing the onset and progression of diabetic cardiomyopathy.

An increase in intercellular crosstalk and electrotonic coupling between cardiomyocytes and nonmyocytes reshapes the electrical conduction in the metabolic heart characterized by short QT intervals in ECGs

“…Nonmyocytes such as myofibroblasts may contribute to arrhythmogenesis by direct electrotonic modulation of conduction besides shortened APDs. Overall, our current experimental data together with an excellent supporting discussion by Phang and co‐workers 67 can present valuable information on how cellular interplay between cardiomyocytes (with a short AP) and nonmyocytes. By using both electrophysiological data performed either in vivo (ECGs) or in vitro (APs and ionic currents) and immunohistochemical data obtained in the heart tissue under an early‐stage MetS, we provided some novel data to demonstrate the possible important roles of cardiac nonmyocyte populations in the regulation of both electrical and biomechanical signaling in the heart through developing an extensive network of intercellular communication to maintain a proper balance among excitable cells, Cx43, and nonmyocytes (Figure 7A).…”

Therapeutic strategies targeting mechanisms of macrophages in diabetic heart disease

“…A central pathogenic mechanism of DHD is the inflammatory response, which exacerbates oxidative stress and endoplasmic reticulum stress [ 9 ]. Macrophages, which execute the inflammatory response, influence the course of DHD through the secretion of various inflammatory factors [ 10 ]. Therefore, a drug therapy targeting macrophages may be a promising new direction for improved DHD treatment.…”

A small erythropoietin derived non-hematopoietic peptide reduces cardiac inflammation, attenuates age associated declines in heart function and prolongs healthspan

“…Cardiac non-myocytes, typically endothelial cells, resident mesenchymal cells and leukocytes are critical for maintaining homeostasis of the heart ( 43 ). However, an increased ratio of cardiac non-myocytes to myocytes has been associated with diastolic dysfunction and pathologic cardiac hypertrophy ( 44 , 45 ). Specifically, established mediators of cardiac hypertrophy such as atrial natriuretic peptide, brain natriuretic peptide and angiotensin-II have shown to increase the ratio of non-myocyte to myocytes ( 46 , 47 ).…”