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.

Keywords: Calcium signaling; Diabetic cardiomyopathy; Exosome; Heart failure; Inflammation; Mitochondrial membrane.

Fig. 1

Potential effects of inflammation,  exosomes, and microRNA (miRNA) on Ca²⁺ transport, storage and mitochondrial Ca²⁺ handling. Excitation–contraction (EC) coupling is initiated by an action potential which depolarizes the sarcolemma by rapid sodium (Na⁺) influx. Depolarization activates voltage-gated L-type Ca²⁺ channels (LTCC), and Ca²⁺ influx triggering calcium-induced calcium release (CICR) from the sarcoplasmic reticulum (SR) via the ryanodine receptor (RyR2). Rapid release of Ca²⁺ from the SR increases free intracellular Ca²⁺, enabling muscle contraction. Cardiomyocyte relaxation is regulated by signaling pathways that restore intracellular and SR Ca²⁺ to resting concentrations. Ca²⁺-activated kinases phosphorylate phospholamban (PLB), relieving its repression on Sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA2a). Consequently, SERCA2a rapidly imports Ca²⁺ into the SR, decreasing the intracellular Ca²⁺ concentration. Na⁺/Ca²⁺ exchangers (NCX) are allosterically activated by Ca²⁺ and aid in restoring resting Ca²⁺ concentrations; decreased cytosolic Ca²⁺ leads to relaxation of the sarcomere. Genes downregulated in DCM are denoted by a blue downward arrow and genes upregulated during DCM are denoted by a red upward arrow. Mitochondria is an energy mobilization and  Ca²⁺-buffering organelle. The Ca²⁺ homeostasis is controlled by its uptake through the mitochondrial Ca²⁺ uniporter (MCU) complex and voltage-dependent channel proteins, Ca²⁺ efflux is controlled by NCX. Exosomes and miRNAs control the gene expression of certain inflammatory cytokines, Ca²⁺ handling and signaling proteins. DHPR Dihydropyridine receptor; BIN1 bridging integrator 1; PMCA Sarcolemmal/plasma membrane Ca²⁺-ATPase; CSQ calsequestrin, mNCX Mitochondrial N⁺/Ca²⁺ exchanger; TNF-α Tumor necrosis factor-α; IL1b Interleukin 1β

Fig. 2

Salient molecular changes in the regulators of the Ca²⁺ transits during excitation-contraction (EC) coupling associated with DCM. Arbitrary separations of the early and late-stage changes are also indicated. These changes eventually lead to the diabetic cardiomyopathic phenotypes, mitochondrial changes, inflammation, and exosome mediated effects on Ca²⁺ transits leading to heart failure. NCX N⁺/Ca²⁺ exchanger; PMCA Sarcolemmal/plasma membrane Ca2⁺-ATPase; SERCA2a Sarco(endo)plasmic reticulum Ca²⁺-ATPase; RYR2 Ryanodine receptor 2; LTCC L-type calcium channels; SR Sarcoplasmic reticulum; MCU Mitochondrial Ca²⁺uniporter; mCa²⁺ mitochondrial Ca²⁺; ROS Reactive oxygen species; mPTP Mitochondrial permeability transition pore; iCa²⁺ Intracellular Ca²⁺; MHC Myosin heavy chain