Mitoprotective antioxidant EUK-134 stimulates fatty acid oxidation and prevents hypertrophy in H9C2 cells

Abstract

Oxidative stress is an important contributory factor for the development of cardiovascular diseases like hypertension-induced hypertrophy. Mitochondrion is the major source of reactive oxygen species. Hence, protecting mitochondria from oxidative damage can be an effective therapeutic strategy for the prevention of hypertensive heart disease. Conventional antioxidants are not likely to be cardioprotective, as they cannot protect mitochondria from oxidative damage. EUK-134 is a salen-manganese complex with superoxide dismutase and catalase activity. The possible role of EUK-134, a mitoprotective antioxidant, in the prevention of hypertrophy of H9C2 cells was examined. The cells were stimulated with phenylephrine (50 μM), and hypertrophy was assessed based on cell volume and expression of brain natriuretic peptide and calcineurin. Enhanced myocardial lipid peroxidation and protein carbonyl content, accompanied by nuclear factor-kappa B gene expression, confirmed the presence of oxidative stress in hypertrophic cells. Metabolic shift was evident from reduction in the expression of medium-chain acyl-CoA dehydrogenase. Mitochondrial oxidative stress was confirmed by the reduced expression of mitochondria-specific antioxidant peroxiredoxin-3 and enhanced mitochondrial superoxide production. Compromised mitochondrial function was apparent from reduced mitochondrial membrane potential. Pretreatment with EUK-134 (10 μM) was effective in the prevention of hypertrophic changes in H9C2 cells, reduction of oxidative stress, and prevention of metabolic shift. EUK-134 treatment improved the oxidative status of mitochondria and reversed hypertrophy-induced reduction of mitochondrial membrane potential. Supplementation with EUK-134 is therefore identified as a novel approach to attenuate cardiac hypertrophy and lends scope for the development of EUK-134 as a therapeutic agent in the management of human cardiovascular disease.

GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling

“…A possible role for lipid modulation exists via the BH 4 -dependent enzyme AGMO; whether this occurs in human patients is unclear . Protecting mitochondrial damage by antioxidants has been shown to increase mitochondrial metabolism, which may consume ferroptosis-sensitive fatty acids …”

Mitochondrial function in the heart: the insight into mechanisms and therapeutic potentials

“…For example, EUK‐8, a SOD and catalase mimetic, has been shown to protect mouse hearts against pressure overload‐induced heart failure and dilated cardiomyopathy (Empel et al ., ; Kawakami et al ., ). EUK‐134, a more lipophilic derivative of EUK‐8, blunts hypertrophic responses in H9C2 cardiac cell lines (Purushothaman and Nair, ). EUK‐134 also prevents diaphragm muscle weakness in the rat model of monocrotalin‐induced pulmonary hypertension (Himori et al ., ).…”

STVNa Attenuates Isoproterenol-Induced Cardiac Hypertrophy Response through the HDAC4 and Prdx2/ROS/Trx1 Pathways

“…Mitochondrial membrane depolarization compromises the respiration function, triggering apoptosis. Normalization of MMP in cells treated with EUK-134 attenuated cardiac hypertrophy [35]. Therefore, we reasoned that STVNa may prevent cardiac hypertrophy by preserving mitochondrial integrity and function.…”