Uryash A, Mijares A, Flores V, Adams J A, Lopez J R
Department of Neonatology, Mount Sinai Medical Center, Miami, FL, United States.
Centro de Biofísica y Bioquímica, Instituto Venezolano de Investigaciones Científicas, Caracas, Venezuela.
Front Pharmacol. 2021 Aug 23;12:719268. doi: 10.3389/fphar.2021.719268. eCollection 2021.
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 Ca concentrations ([Ca]), 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 (K) channels. Treatment of T2D mice with the citrus fruit flavonoid naringin for 4 weeks protected cardiomyocytes by reducing diastolic Ca 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 K channels. Administration of the K channel inhibitor glibenclamide caused a further increase in [Ca] in T2D cardiomyocytes and abolished the naringin effect on [Ca]. Nicorandil, a K channel opener, and nitric oxide donor drug mimic the naringin effect on [Ca] 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.
糖尿病性心肌病（DCM）是糖尿病患者的一种原发性疾病，其特征为舒张功能障碍，可导致心力衰竭和死亡。不幸的是，即使严格控制血糖也未能有效预防该病。我们在2型糖尿病（T2D）小鼠模型（db/db）的心肌细胞中发现，舒张期钙离子浓度（[Ca]）异常、葡萄糖转运减少、活性氧（ROS）生成增加以及钙蛋白酶活性增强。这些小鼠的心肌细胞表现出明显的细胞损伤、肿瘤坏死因子-α和白细胞介素-6水平升高以及转录核因子-κB（NF-κB）的表达。此外，细胞活力降低，ATP敏感性钾（K）通道的Kir6.2、SUR1和SUR2亚基的表达减少。用柑橘类水果黄酮柚皮苷对T2D小鼠进行4周治疗，可通过减少舒张期钙超载、改善葡萄糖转运、降低活性氧生成以及抑制心肌炎症来保护心肌细胞。此外，柚皮苷降低了钙蛋白酶活性，减少了心脏损伤，增加了细胞活力，并恢复了K通道Kir6.2、SUR1和SUR2亚基的蛋白表达。给予K通道抑制剂格列本脲会使T2D心肌细胞中的[Ca]进一步升高，并消除柚皮苷对[Ca]的作用。钾通道开放剂和一氧化氮供体药物尼可地尔模拟了柚皮苷对T2D心肌细胞中[Ca]的作用；然而，它加重了T2D小鼠的高血糖症。这些数据为柚皮苷对T2D心肌病有益作用的潜在机制提供了新的见解，从而提示了一种治疗这种心血管并发症的新方法。
