Exercise Training Promotes Cardiac Hydrogen Sulfide Biosynthesis and Mitigates Pyroptosis to Prevent High-Fat Diet-Induced Diabetic Cardiomyopathy

Abstract

Obesity increases the risk of developing diabetes and subsequently, diabetic cardiomyopathy (DMCM). Reduced cardioprotective antioxidant hydrogen sulfide (H 2 S) and increased inflammatory cell death via pyroptosis contribute to adverse cardiac remodeling and DMCM. Although exercise training (EX) has cardioprotective effects, it is unclear whether EX mitigates obesity-induced DMCM by increasing H 2 S biosynthesis and mitigating pyroptosis in the heart. C57BL6 mice were fed a high-fat diet (HFD) while undergoing treadmill EX for 20 weeks. HFD mice developed obesity, hyperglycemia, and insulin resistance, which were reduced by EX. Left ventricle pressure-volume measurement revealed that obese mice developed reduced diastolic function with preserved ejection fraction, which was improved by EX. Cardiac dysfunction was accompanied by increased cardiac pyroptosis signaling, structural remodeling, and metabolic remodeling, indicated by accumulation of lipid droplets in the heart. Notably, EX increased cardiac H 2 S concentration and expression of H 2 S biosynthesis enzymes. HFD-induced obesity led to features of type 2 diabetes (T2DM), and subsequently DMCM. EX during the HFD regimen prevented the development of DMCM, possibly by promoting H 2 S-mediated cardioprotection and alleviating pyroptosis. This is the first report of EX modulating H 2 S and pyroptotic signaling in the heart. mechanisms induced by EX to ameliorate cardiac dysfunction would lead to novel therapeutic targets for DMCM-especially in patients unable to exercise.Cardiomyocyte cell death is a key molecular event in the progression of DMCM, as the death of terminally differentiated cardiomyocytes leads to loss of contractile units and instigates fibrosis [12]. In metabolic syndrome, the diabetic environment of hyperglycemia, inflammatory cytokines, oxidative damage, and lipotoxicity induces several types of cell death, including non-inflammatory (apoptosis), and inflammatory (pyroptosis) cell death in the heart [13][14][15]. Pyroptosis is an inflammasome-mediated cell death mechanism where activation of the NOD-like receptor protein 3 (NLRP3) inflammasome activates caspase-1 and results in cell lysis and release of the interleukin IL-1β [16]. Hyperglycemia, fatty acids, and oxidative stress activate NLRP3 and caspase-1-mediated inflammasome, and inhibition of NLRP3 mitigates DMCM in diabetic rats [17][18][19]. Furthermore, HFD and obesity lead to inflammasome activation and infiltration of macrophages into adipose tissue, the key player in pyroptosis [18,20]. However, the role of pyroptosis in obesity-induced cardiac remodeling is unclear. Vandanmagsar et al. demonstrated that EX reduces pyroptotic cell death in adipose and liver tissue, however, this effect has not been evaluated in the heart [18].Hydrogen sulfide (H 2 S), a cardioprotective gaseous signaling molecule produced by homocysteine transsulfuration, prevents adverse cardiac remodeling and cell death, including pyroptosis [21]. H 2 S inhibits caspase-1 activity and IL-1β secretion both in vit...

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