Hydrogen sulfide attenuates high fat diet-induced cardiac dysfunction via the suppression of endoplasmic reticulum stress
Introduction
Cardiovascular disease refers to any disease that affects the cardiovascular system, including cardiac disease, vascular diseases of the brain and kidney, and peripheral artery disease. Worldwide, it is on the rise and continues to be the leading cause of morbidity and mortality in both men and women [1]. A major contributor to the rise in cardiovascular disease is the increased prevalence of diabetes mellitus [2]. According to the World Health Organization, diabetes affects 347 million people worldwide (http://www.who.int/mediacentre/factsheets/fs312/en/). Diabetes is responsible for diverse cardiovascular complications, such as hypertension, atherosclerosis, and heart failure [3]. Additionally, diabetes and insulin resistance are powerful predictors of cardiovascular morbidity and mortality, as well as independent risk factors for death in patients with established heart failure [4], [5]. Diabetes can also affect cardiac structure and function in the absence of changes in blood pressure and coronary artery disease [3], a condition termed “diabetic cardiomyopathy” [6]. The pathophysiology of diabetic cardiomyopathy is multifactorial with evidence that autonomic dysfunction, metabolic derangements, and the development of interstitial fibrosis all contribute to myocardial stiffness and impaired contractility [3], [7], [8]. However, the molecular mechanisms that underlie the development of diabetic cardiomyopathy require further investigation.
The endoplasmic reticulum (ER) is the central organelle for secretory/transmembrane protein folding, calcium storage, and lipid synthesis [2]. Pathological stimuli such as oxidative stress, the accumulation of lipids, and the accumulation of misfolded proteins interfere with the function of the ER [9]. As a result, ER stress develops and the unfolded protein response (UPR) is triggered [10]. In an effort to ameliorate ER stress, the UPR activates three pathways to antagonize the cellular stress. As an initial step, the chaperone protein BiP (GRP78) senses unfolded or damaged proteins. It then subsequently activates PKR-like ER kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). Engagement of the ER stress/UPR response acutely reduces protein synthesis in the ER, enhances protein degradation of damaged or misfolded proteins, and selectively induces expression of protective proteins [11], [12]. While the acute activation of the ER stress/UPR is protective, prolonged activation triggers an apoptotic-signaling cascade resulting in cell death [9]. Mounting evidence suggests that ER stress/UPR plays a critical role in the heart during the development of diabetic cardiomyopathy [2], [9]. For instance, markers of ER stress are elevated in the hearts of diabetic animals [13], [14], [15] and therapeutic strategies that manipulate components of the ER stress response improve cardiac function in the setting of diabetes [16], [17]. This suggests that targeting ER stress may be a viable treatment option to prevent or attenuate the development of diabetic cardiomyopathy.
Hydrogen sulfide (H2S) is an endogenously produced gaseous signaling molecule that is critical for the regulation of cardiovascular homeostasis [18], [19]. Recently, therapeutic strategies aimed at increasing the levels of H2S have been shown to be cardioprotective in models of acute myocardial ischemia–reperfusion (MI/R) injury and heart failure [20], [21], [22], [23]. These cytoprotective effects are attributed to the ability of H2S to upregulate antioxidant defenses and to reduce apoptosis, inflammation, and mitochondrial injury [24]. In brief, cardiomyopathic oxidative stress states cause an increase in reactive oxygen species (ROS) production, leading to mitochondrial damage, lipid peroxidation, and DNA strand breaks. These and related maladaptations are mitigated by antioxidants, which scavenge and neutralize the ROS [25]. H2S has been found to upregulate antioxidant properties, attenuating the adverse effects of oxidative stress [26]. Increasing evidence suggests an association between oxidative stress and the progression of diabetic complications in various tissues, including the heart [27], [28], [29]. Thus, the reported antioxidant effects of H2S may be of critical importance in the diabetic myocardium. However, circulating levels of H2S are decreased in animal models of diabetes [30], [31], [32], [33] and in T2DM patients [30], [34]. Previous work from our lab found that lower levels of H2S are not confined to the circulation in the setting of diabetes, as evidenced by the findings that cardiac levels of H2S were also decreased in db/db diabetic mice [35]. Furthermore, we found that treatment with exogenous H2S for 7 days increased cardiac H2S levels and reduced myocardial injury following I/R. This latter finding supports the idea that decreased H2S levels in the setting of diabetes contribute to the pathophysiology of the disease [36], especially in relation to cardiovascular complications.
To our knowledge, 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. In addition, we investigated if H2S therapy ameliorated the development of diabetic cardiomyopathy by decreasing ER stress.
Section snippets
Animals
Male C57BL/6J mice were purchased from The Jackson Laboratory (Bar Harbor, ME) at 6 weeks of age. Starting at 8 weeks of age, different groups of mice were maintained on one of the following diets for 24 weeks: (1) Control Diet (10% fat diet, Open Source Diets D12450Bi), (2) High Fat Diet (HFD, 60% fat; Open Source Diets D12492i), or (3) HFD supplemented with SG-1002, an orally active H2S donor. SG-1002 (provided by Sulfagenix, Cleveland, OH) was added to the HFD mice to achieve a dosage of
Oral H2S therapy ameliorates HFD-induced cardiac dysfunction
Our initial experiments examined the effects of HFD feeding on the myocardial expression of the three known H2S-producing enzymes, as well as the levels of circulating and myocardial sulfide levels. As expected, HFD feeding for 24 weeks induced increases in body weight, serum glucose levels, glucose intolerance, serum insulin levels, and serum cholesterol levels, recapitulating hallmark features of type-2 diabetes (Table 1 and Supplemental Fig. S2). Immunoblot analysis of whole cell extracts
Discussion
Diabetic cardiomyopathy is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome [4]. However, the underlying molecular mechanisms leading to the development of diabetic cardiomyopathy have not been fully elucidated. The results of the current study suggest that diminished circulating and cardiac H2S levels play a role in the pathophysiology of HFD-induced cardiomyopathy. Our findings support the following conclusions: (1) HFD feeding decreases
Acknowledgments
This work was supported by a grant from the National Institutes of Health, National Heart, Lung, and Blood Institute (5R01HL098481-05) to J.W.C. This work was also supported by funding from the Carlyle Fraser Heart Center of Emory University Hospital Midtown.
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