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Cardioprotective role of SIRT1 activation on mitochondrial function in insulin-resistant H9c2 cells
Buğrahan Sancak1, Deniz İnönü1, Gülsüm Alp1
1Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Türkiye.
Background:
Insulin-resistance in cardiomyocytes is often associated with metabolic disorders like obesity, and type2 diabetes. Studies demonstrated that sirtuin1 (SIRT1) plays a protective role in cells resistant to insulin by enhancing insulin sensitivity and improving glucose metabolism. Based on these protective functions observed in SIRT1, this study aims to investigate the roles of SIRT1 in palmitate (PA)-induced insulin-resistant H9C2 cells.
Methods:
Insulin-resistance was induced in H9c2 cells via incubation with palmitic acid (50µM;24 h). Control and Insulin-resistant cells were incubated with SIRT1 inhibitor (EX527;10µM) and SIRT1 activator (SRT1720;2µM) for 24 h, respectively. Mitochondrial membrane potential (MMP), reactive oxygen/nitrogen species (ROS/RNS), total ATP production, intracellular free zinc and calcium levels ([Ca2+]i and [Zn2+]i) were monitored with fluorescence techniques. Protein levels were determined by using western-blot analysis.
Results:
K-acetylation level was increased in PA-induced Insulin-resistant cells and SIRT1 inhibited control cells. ROS/RNS production, [Ca2+]i, and [Zn2+]i levels were elevated, MMP was depolarized and ATP production was decreased in PA and EX527 treated cells compared to control cells. Mfn1 and Fis1 levels were remained unchanged, however Mfn2 protein level was elevated in cells treated with PA and SIRT1 inhibitor. Nevertheless, anti- and pro-apoptotic protein level was reduced and augmented respectively in insulin-resistant and SIRT1 inhibited cells. Activation of SIRT1 in PA-treated cells restored mitochondrial function and intracellular ionic homeostasis, reduced K-acetylation, and mitigated apoptosis.
Conclusion:
Therefore, it can be proposed that the activation of SIRT1, acting as a novel regulator, may offer direct cardioprotection by restoring mitochondrial function in the insulin-resistant heart.
Insights
Sirtuin1 (SIRT1) activation protects heart cells from insulin resistance by restoring mitochondrial function and reducing apoptosis. This study highlights SIRT1
Area of Science:
- Cardiovascular Biology
- Metabolic Disease Research
- Cellular Metabolism
Background:
- Insulin resistance in cardiomyocytes is linked to obesity and type 2 diabetes.
- Sirtuin1 (SIRT1) enhances insulin sensitivity and glucose metabolism.
- This study investigates SIRT1's role in palmitate-induced insulin-resistant H9C2 cells.
Purpose of the Study:
- To explore the function of SIRT1 in palmitate-induced insulin resistance in H9C2 cardiomyocytes.
- To determine if SIRT1 activation can reverse detrimental effects of insulin resistance on cellular function.
Main Methods:
- Insulin resistance was induced in H9C2 cells using palmitic acid (PA).
- Cells were treated with a SIRT1 inhibitor (EX527) or activator (SRT1720).
- Mitochondrial function, reactive oxygen/nitrogen species (ROS/RNS), ATP production, and ion levels were assessed.
Main Results:
- Palmitate-induced insulin resistance increased K-acetylation, ROS/RNS, calcium, and zinc levels, while decreasing mitochondrial membrane potential and ATP production.
- SIRT1 inhibition exacerbated these negative effects.
- SIRT1 activation in insulin-resistant cells restored mitochondrial function, ionic homeostasis, and reduced apoptosis.
Conclusions:
- SIRT1 activation mitigates palmitate-induced cellular damage in cardiomyocytes.
- SIRT1 acts as a cardioprotective regulator by restoring mitochondrial function in insulin-resistant hearts.
