The interplay of inflammation, exosomes and Ca2+ dynamics in diabetic cardiomyopathy

Abstract

Diabetes mellitus is one of the prime risk factors for cardiovascular complications and is linked with high morbidity and mortality. Diabetic cardiomyopathy (DCM) often manifests as reduced cardiac contractility, myocardial fibrosis, diastolic dysfunction, and chronic heart failure. Inflammation, changes in calcium (Ca2+) handling and cardiomyocyte loss are often implicated in the development and progression of DCM. Although the existence of DCM was established nearly four decades ago, the exact mechanisms underlying this disease pathophysiology is constantly evolving. Furthermore, the complex pathophysiology of DCM is linked with exosomes, which has recently shown to facilitate intercellular (cell-to-cell) communication through biomolecules such as micro RNA (miRNA), proteins, enzymes, cell surface receptors, growth factors, cytokines, and lipids. Inflammatory response and Ca2+ signaling are interrelated and DCM has been known to adversely affect many of these signaling molecules either qualitatively and/or quantitatively. In this literature review, we have demonstrated that Ca2+ regulators are tightly controlled at different molecular and cellular levels during various biological processes in the heart. Inflammatory mediators, miRNA and exosomes are shown to interact with these regulators, however how these mediators are linked to Ca2+ handling during DCM pathogenesis remains elusive. Thus, further investigations are needed to understand the mechanisms to restore cardiac Ca2+ homeostasis and function, and to serve as potential therapeutic targets in the treatment of DCM.

Distribution and prognostic value of high-sensitivity cardiac troponin T and I across glycemic status: a population-based study

“…Indeed, hs-cTnI and hs-cTnT were comparably correlated with CRP in hyperglycemic populations while in the normoglycemic population hs-cTnI but not hs-cTnT was correlated with CRP. As inflammation played an important role in the development of diabetic cardiomyopathy [ 40 ], this finding suggested inflammation might serve as a common pathway that concordantly increased concentrations of hs-cTnT and hs-cTnI in hyperglycemic populations.…”

Progress in the treatment of diabetic cardiomyopathy, a systematic review

“…17,20,29 Nevertheless, the novel therapeutic gene, calcium-binding protein S100A1, regulates the Ca 2+ -related pathway, increases mitochondrial adenosine triphosphate production, enhances energy supply to myocardial cells, and reinforces myocardial cell contractility. [30][31][32] Experimental evidence indicates that repairing and overexpressing S100A1 in rodent and pig myocardium suggests its potential to improve both systolic and diastolic functions of the heart. 32 However, gene therapy for DCM is still in its nascent stage, and further extensive research and clinical trials are required to assess its safety and efficacy.…”

“…The absence of large‐scale cardiac clinical trials and the high prevalence of existing antibodies against many AAV serotypes are current issues 17,20,29 . Nevertheless, the novel therapeutic gene, calcium‐binding protein S100A1, regulates the Ca 2+ ‐related pathway, increases mitochondrial adenosine triphosphate production, enhances energy supply to myocardial cells, and reinforces myocardial cell contractility 30–32 . Experimental evidence indicates that repairing and overexpressing S100A1 in rodent and pig myocardium suggests its potential to improve both systolic and diastolic functions of the heart 32 …”

Central role of cardiac fibroblasts in myocardial fibrosis of diabetic cardiomyopathy

“…Interleukin (IL) is an important type of inflammatory cytokine. A variety of interleukin receptors are expressed in CFs, which regulate the activity of myofibroblasts (10, 22,180,181). It was found that the expressions of IL-6 (133), IL-17 (182), IL-1b (162) and IL-33 (183) were all up-regulated in myocardial fibroblasts attacked by HG, and loss of these inflammatory factors could reduce the collagen expression induced by HG.…”

“…Both in human patients and in animal models of diabetes, cardiac fibrosis is prominent characteristic of diabetic cardiomyopathy (19,20). As the main ECM-producing cells in the heart, CFs are critically involved in all cardiac fibrotic conditions (21,22). For these reasons, an in-depth understanding of the character of CFs in myocardial fibrosis in DCM may point the direction for formulating strategies to prevent and treat myocardial fibrosis.…”