Barr Larry A, Shimizu Yuuki, Lambert Jonathan P, Nicholson Chad K, Calvert John W
Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, USA.
Department of Surgery, Division of Cardiothoracic Surgery, Carlyle Fraser Heart Center, Emory University School of Medicine, Atlanta, GA, USA.
Nitric Oxide. 2015 Apr 30;46:145-56. doi: 10.1016/j.niox.2014.12.013. Epub 2015 Jan 6.
Diabetic cardiomyopathy is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. However, the underlying molecular mechanisms that lead to its development have not been fully elucidated. Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that is critical for the regulation of cardiovascular homeostasis. Recently, therapeutic strategies aimed at increasing its levels have proven cardioprotective in models of acute myocardial ischemia-reperfusion injury and heart failure. The precise role of H2S in the pathogenesis of diabetic cardiomyopathy has not yet been established. Therefore, the goal of the present study was to evaluate circulating and cardiac H2S levels in a murine model of high fat diet (HFD)-induced cardiomyopathy. Diabetic cardiomyopathy was produced by feeding mice HFD (60% fat) chow for 24 weeks. HFD feeding reduced both circulating and cardiac H2S and induced hallmark features of type-2 diabetes. We also observed marked cardiac dysfunction, evidence of cardiac enlargement, cardiac hypertrophy, and fibrosis. H2S therapy (SG-1002, an orally active H2S donor) restored sulfide levels, improved some of the metabolic perturbations stemming from HFD feeding, and attenuated HFD-induced cardiac dysfunction. Additional analysis revealed that H2S therapy restored adiponectin levels and suppressed cardiac ER stress stemming from HFD feeding. These results suggest that diminished circulating and cardiac H2S levels play a role in the pathophysiology of HFD-induced cardiomyopathy. Additionally, these results suggest that H2S therapy may be of clinical importance in the treatment of cardiovascular complications stemming from diabetes.
糖尿病性心肌病是导致糖尿病和代谢综合征发病及死亡的重要因素。然而，导致其发生发展的潜在分子机制尚未完全阐明。硫化氢（H₂S）是一种内源性产生的信号分子，对心血管稳态的调节至关重要。最近，旨在提高其水平的治疗策略已被证明在急性心肌缺血再灌注损伤和心力衰竭模型中具有心脏保护作用。H₂S在糖尿病性心肌病发病机制中的具体作用尚未确定。因此，本研究的目的是评估高脂饮食（HFD）诱导的心肌病小鼠模型中循环和心脏H₂S水平。通过给小鼠喂食HFD（60%脂肪）饲料24周来诱导糖尿病性心肌病。喂食HFD降低了循环和心脏中的H₂S水平，并诱发了2型糖尿病的标志性特征。我们还观察到明显的心脏功能障碍、心脏扩大、心肌肥大和纤维化的证据。H₂S治疗（SG - 1002，一种口服活性H₂S供体）恢复了硫化物水平，改善了一些由HFD喂养引起的代谢紊乱，并减轻了HFD诱导的心脏功能障碍。进一步分析表明，H₂S治疗恢复了脂联素水平，并抑制了HFD喂养引起的心脏内质网应激。这些结果表明，循环和心脏中H₂S水平的降低在HFD诱导的心肌病病理生理学中起作用。此外，这些结果表明，H₂S治疗在治疗糖尿病引起的心血管并发症方面可能具有临床重要性。
