A novel SOD mimic with a redox-modulating mn (II) complex, ML1 attenuates high glucose-induced abnormalities in intracellular Ca 2+ transients and prevents cardiac cell death through restoration of mitochondrial function

Abstract

A key contributor to the pathophysiology of diabetic cardiomyopathy, mitochondrial superoxide can be adequately countered by Mn-superoxide dismutase, which constitutes the first line of defense against mitochondrial oxidative stress. Our group has recently synthesized low molecular weight SOD mimics, demonstrating superior protection against oxidative damages to kidney cells. In the current study, we sought to evaluate the protective effect of the SOD mimic ML1 against high glucose induced cardiomyopathy in diabetes. Mechanistic studies using rat cardiac myoblast H9c2 showed that ML1 markedly inhibited High Glucose (HG) induced cytotoxicity. This was associated with increased Mn-SOD expression along with decreased mitochondrial 90%90%O2prefix·prefix-, ONOO- and Ca2+ accumulation, unveiling its anti-oxidant potentials. ML1 also attenuated HG-induced loss of mitochondrial membrane potential (ΔΨm) and release of cytochrome c, suggesting that ML1 effectuates its cytoprotective action via the preservation of mitochondrial function. In an ex-vivo model normal adult rat ventricular myocytes (ARVMs) were isolated and cultured in either normal glucose (5.5 mmol/l glucose) or HG (25.5 mmol/l glucose) conditions and the efficiency of ML-1 was analyzed by studying contractile function and calcium indices. Mechanical properties were assessed using a high-speed video-edge detection system, and intracellular Ca2+ transients were recorded in fura-2–loaded myocytes. Pretreatment of myocytes with ML1 (10 nM) ameliorated HG induced abnormalities in relaxation including depressed peak shortening, prolonged time to 90% relenghthening, and slower Ca2+ transient decay. Thus, ML1 exhibits significant cardio protection against oxidative damage, perhaps through its potent antioxidant action via activation of Mn-SOD.

Tianhuang formula regulates adipocyte mitochondrial function by AMPK/MICU1 pathway in HFD/STZ-induced T2DM mice

“…At the same time, MCU and MICU1 are major highly selective channels for m Ca 2+ uptake, and the transportation of Ca 2+ depends on the electrochemical gradient of MMP [ 38 ]. In a high glucose environment, the MMP of 3T3-L1 adipocytes decreases, forming a vicious cycle [ 39 ]. Previous studies have shown that m Ca 2+ effects membrane potential and ATP production.…”

The mitochondrial calcium uniporter induces apoptosis in cardiomyocytes cultured with high-glucose medium by affecting mitochondrial function

“…Previous studies have shown that after the application of MCU inhibitors, mitochondrial calcium homeostasis has been disturbed and further led to mitochondrial oxidative respiratory dysfunction and membrane potential loss [26] . Mitochondrial Ca 2+ uptake depends on the mitochondrial membrane potential, and the myocardial cell mitochondrial membrane potential decreases in a high-glucose environment, thus forming a vicious cycle, which ultimately leads to cell apoptosis [27] . The present experimental results showed that the calcium homeostasis high glucose group H9C2 cardiomyocytes had reduced ATP production, decreased membrane potential, and increased apoptosis.…”