High glucose induced calcium overload via impairment of SERCA/PLN pathway and mitochondrial dysfunction leads to oxidative stress in H9c2 cells and amelioration with ferulic acid

Abstract

Oxidative stress and associated complications are the major pathological concerns of diabetic cardiomyopathy (DC). We aim to elucidate the mechanisms by which high glucose (HG) induced alteration in calcium homeostasis and evaluation of the beneficial effect of two concentrations (10 and 25 μm) of ferulic acid (FA). HG was induced in H9c2 cardiomyoblast by treating with glucose (33 mm) for 48 h, and FA was co‐treated. Intracellular calcium ([Ca2+]i) overload was found increased significantly with HG. For elucidation of mechanism, the SERCA pathway and mitochondrial integrity (transmembrane potential and permeability transition pore) were explored. Then, we assessed oxidative stress, and cell injury with brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), and lactate dehydrogenase (LDH) release. HG caused significant [Ca2+]i overload through downregulation of SERCA2/1, pPLN, and pPKA C‐α; and upregulation of PLN and PKA C‐α and alteration in the integrity of mitochondria with HG. The [Ca2+]i overload in turn caused oxidative stress via generation of reactive oxygen species, lipid peroxidation, and protein carbonylation. This resulted in cell injury which was evident with significant release of BNP, ANP, and LDH. FA co‐treatment was effective to mitigate all pathological changes caused by HG. From the overall results, we conclude that [Ca2+]i overload via SERCA pathway and altered mitochondrial integrity is the main cause for oxidative stress during HG. Based on our result, we report that FA could be an attractive nutraceutical for DC.

Implication of dietary phenolic acids on inflammation in cardiovascular disease

“…In a doxorubicin induced cardiotoxicity model, ferulic acid inhibits cardiac apoptosis and oxidative stress via regulation of MAPK activation, NF-κB pathway and PI3K/Akt/mTOR impairment (Sahu et al, 2019). Lastly, ferulic acid ameliorates high glucose-induced oxidative stress and calcium overload via modulation of the mitochondrial function and SERCA/PLN pathway in H9c2 cardiomyoblast (Salin Raj et al, 2019).…”

Pathophysiology, Clinical Characteristics of Diabetic Cardiomyopathy: Therapeutic Potential of Natural Polyphenols

“…In cardiac H9C2 cells, gallic acid was found to suppress hypertrophy and fibrosis by regulating JNK2 signaling and Smad3 binding. In these cells, ferulic acid was also shown to protect cardiomyoblasts from high glucose induced oxidative stress by mediating Ca 2+ homeostasis (68). Similarly, epigallocatechin-3-gallate mediated cardioprotection was observed through Akt/GSK-3β/caveolin signaling (69).…”

Ferulic acid attenuates high glucose-induced apoptosis in retinal pigment epithelium cells and protects retina in db/db mice

“…Besides ARPE-19 cells, FA increases cell viability and reduces apoptosis of hepatocytes and cardiomyocytes exposed to HG ( Song et al, 2016 ). FA improves HG-induced oxidative stress in H9C2 cells ( Salin Raj, Swapna & Raghu, 2019 ). Mechanistically, we found that FA can prevent HG-induced increase in BAX (pro-apoptosis) and decrease in Bcl-2 (anti-apoptosis).…”