Diastolic dysfunction in prediabetic male rats: Role of mitochondrial oxidative stress

Abstract

Although incidence and prevalence of prediabetes are increasing, little is known about its cardiac effects. Therefore, our aim was to investigate the effect of prediabetes on cardiac function and to characterize parameters and pathways associated with deteriorated cardiac performance. Long-Evans rats were fed with either control or high-fat chow for 21 wk and treated with a single low dose (20 mg/kg) of streptozotocin at week 4 High-fat and streptozotocin treatment induced prediabetes as characterized by slightly elevated fasting blood glucose, impaired glucose and insulin tolerance, increased visceral adipose tissue and plasma leptin levels, as well as sensory neuropathy. In prediabetic animals, a mild diastolic dysfunction was observed, the number of myocardial lipid droplets increased, and left ventricular mass and wall thickness were elevated; however, no molecular sign of fibrosis or cardiac hypertrophy was shown. In prediabetes, production of reactive oxygen species was elevated in subsarcolemmal mitochondria. Expression of mitofusin-2 was increased, while the phosphorylation of phospholamban and expression of Bcl-2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3, a marker of mitophagy) decreased. However, expression of other markers of cardiac auto- and mitophagy, mitochondrial dynamics, inflammation, heat shock proteins, Ca/calmodulin-dependent protein kinase II, mammalian target of rapamycin, or apoptotic pathways were unchanged in prediabetes. This is the first comprehensive analysis of cardiac effects of prediabetes indicating that mild diastolic dysfunction and cardiac hypertrophy are multifactorial phenomena that are associated with early changes in mitophagy, cardiac lipid accumulation, and elevated oxidative stress and that prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria.

Hypercholesterolemia downregulates autophagy in the rat heart

“…Recently we showed that diet-induced obesity leads to decreased induction of autophagy in response to fasting in mice involving altered expression of numerous proteins related to metabolic pathways [15], which is in parallel to our current findings. However, in Long-Evans rats fed with high-fat diet we demonstrated only early signs of decreased mitophagy, but no major changes in overall cardiac autophagy or mTOR pathway [38]. In contrast, elsewhere metabolic syndrome induced by high-fat feeding increased cardiac LC3-II and SQSTM1/p62 in mice [39].…”

Dihydromyricetin Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Mice

“…Increased ROS production in the diabetic heart is a contributing factor in the development and progression of DCM. Koncsos et al reported that mild diastolic dysfunction and cardiac hypertrophy are associated with elevated oxidative stress in prediabetes, and prediabetes-induced oxidative stress originates from the subsarcolemmal mitochondria [15]. When ROS generation and ROS-degrading pathways are imbalanced, superoxide-mediated damage and cellular dysfunction will accumulate [16, 17].…”

Role of Mitophagy in Cardiovascular Disease

“…Relative to the control, the contents of mitophagy-related proteins were significantly altered in several diabetic tissues including the heart. In male prediabetic rats, the generation of mitochondrial ROS increased and BNIP3 was downregulated in comparison with the corresponding values in the controls [14,114]. In types 1 and 2 diabetes models, PINK1 and Parkin were downregulated [109,115,116].…”