Abstract
Diabetic cardiomyopathy (DCM) is a primary disease in diabetic patients characterized by diastolic dysfunction leading to heart failure and death. Unfortunately, even tight glycemic control has not been effective in its prevention. We have found aberrant diastolic Ca2+ concentrations ([Ca2+]d), decreased glucose transport, elevated production of reactive oxygen species (ROS), and increased calpain activity in cardiomyocytes from a murine model (db/db) of type 2 diabetes (T2D). Cardiomyocytes from these mice demonstrate significant cell injury, increased levels of tumor necrosis factor-alpha and interleukin-6 and expression of the transcription nuclear factor-κB (NF-κB). Furthermore, decreased cell viability, and reduced expression of Kir6.2, SUR1, and SUR2 subunits of the ATP-sensitive potassium (KATP) channels. Treatment of T2D mice with the citrus fruit flavonoid naringin for 4 weeks protected cardiomyocytes by reducing diastolic Ca2+ overload, improving glucose transport, lowering reactive oxygen species production, and suppressed myocardial inflammation. In addition, naringin reduced calpain activity, decreased cardiac injury, increased cell viability, and restored the protein expression of Kir6.2, SUR1, and SUR2 subunits of the KATP channels. Administration of the KATP channel inhibitor glibenclamide caused a further increase in [Ca2+]d in T2D cardiomyocytes and abolished the naringin effect on [Ca2+]d. Nicorandil, a KATP channel opener, and nitric oxide donor drug mimic the naringin effect on [Ca2+]d in T2D cardiomyocyte; however, it aggravated the hyperglycemia in T2D mice. These data add new insights into the mechanisms underlying the beneficial effects of naringin in T2D cardiomyopathy, thus suggesting a novel approach to treating this cardiovascular complication.
Highlights
Type 2 Diabetes mellitus (T2D) is public health threat with a significant increase in affected individuals worldwide in the last decade (Zimmet et al, 2016)
Our results demonstrate that the naringin exerts cardioprotection through multiple mechanisms 1) Reducing [diastolic calcium concentration (Ca2+]d); 2) Improving cardiomyocyte glucose uptake; 3) Decreasing production reactive oxygen species (ROS); 4) Reducing the level of myocardial tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and the expression of nuclear factor-κB (NF-κB); 5) Attenuating calpain activity, cardiac injury and improving cardiomyocyte viability; 6) Increasing the expression of Kir6.2, SUR1, and SUR2 subunits of the ATP-sensitive potassium (KATP) channels
Our results revealed that TNF-α and IL-6, and NF-κB were elevated in the T2D myocardium, which confirms the involvement of inflammation in the pathogenesis of diabetesinduced cardiac injury (Grubic Rotkvic et al, 2021)
Summary
Type 2 Diabetes mellitus (T2D) is public health threat with a significant increase in affected individuals worldwide in the last decade (Zimmet et al, 2016). Epidemiologic data show that the frequency of heart diseases in diabetic patients is much higher, and the prognosis is worse than in populations without diabetes (Thrainsdottir et al, 2005; Lehrke and Marx, 2017; Singh et al, 2018). One significant complication associated with type 2 diabetes is diabetic cardiomyopathy (DCM), characterized by diastolic dysfunction, ventricular hypertrophy, and interstitial fibrosis leading to heart failure in the absence of dyslipidemia, hypertension and coronary artery disease (Nicolino et al, 1995; Redfield et al, 2003; Singh et al, 2018; Dillmann, 2019). Management of T2D DCM involves lifestyle modifications, including diet, regular physical activity, and pharmacological therapies for glucose management, lipid abnormalities, hypertension, and cardiac failure (Pappachan et al, 2013). Despite decades of intense clinical research, no therapies have substantially protected DCM development in diabetic patients
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