Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes

Abstract

The clinical correlations linking diabetes with accelerated atherosclerosis, cardiomyopathy, and increased post-MI fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in ROS production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP ribose) polymerase (PARP), which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and PARP also reduce sirtuin, PGC1α, and AMPK activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of pro-atherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, PAD4, and activates the NRLP3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of FOXO1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after MI by increasing post-translational protein modifications which cause increased ryanodine receptor phosphorylation and downregulation of SERCA2a transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor α3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy.

MiR-21 protected against diabetic cardiomyopathy induced diastolic dysfunction by targeting gelsolin

“…But the roles of miRNAs in diabetes and its cardiovascular complications are not fully discovered [18–20]. It was reported that miR-195 increased ROS production via Sirt1 and Bcl-2, and inhibition of miR-195 may be a promising therapeutic strategy for lipotoxic cardiomyopathy [21].…”

Is insulin pro-atherogenic at the cellular level?

“…Since hyperinsulinemia is associated with increased cardiovascular risk, hyperinsulinemia and hepatic portal hypoinsulinemia due to injection of insulin preparations widely used in the treatment of type 1 diabetic patients could be responsible, at least in part, for cardiovascular consequences of the disease. The results of epidemiological studies and experimental studies in animal models supported systemic hyperinsulinemia as a major plausible factor in the development of atherosclerosis in diabetic patients [6][7][8][9][10] . Insulin resistance is strongly associated with hyperinsulinemia, and is considered as the major pathologic mechanism for susceptibility to premature atherosclerosis and cardiovascular disease [11,12] .…”

Snapshots: Endoplasmic Reticulum Stress in Lipid Metabolism and Cardiovascular Disease

“…Elevated ERS response in maternal mice with type 2 diabetes mellitus (T2DM) triggers postnatal congenial heart failure (CHD) by inducing ERS, which is evidenced by elevated CHOP, BiP, and XBP1 levels. This indicates that proper hypoglycemic management of pregnant women could reduce the prevalence of cardiovascular risk for the fetus, partially due to suppressed ERS under normal blood glucose conditions (Shah et al, 2016;Wu et al, 2016).…”