Vascular hyperacetylation is associated with vascular smooth muscle dysfunction in a rat model of non-obese type 2 diabetes

Abstract

Background Advanced type 2 diabetes mellitus (T2DM) accelerates vascular smooth muscle cell (VSMC) dysfunction which contributes to the development of vasculopathy, associated with the highest degree of morbidity of T2DM. Lysine acetylation, a post-translational modification (PTM), has been associated with metabolic diseases and its complications. Whether levels of global lysine acetylation are altered in vasculature from advanced T2DM remains undetermined. We hypothesized that VSMC undergoes dysregulation in advanced T2DM which is associated with vascular hyperacetylation. Methods Aged male Goto Kakizaki (GK) rats, a non-obese murine model of T2DM, and age-matched male Wistar rats (control group) were used in this study. Thoracic aortas were isolated and examined for measurement of global levels of lysine acetylation, and vascular reactivity studies were conducted using a wire myograph. Direct arterial blood pressure was assessed by carotid catheterization. Cultured human VSMCs were used to investigate whether lysine acetylation participates in high glucose-induced reactive oxygen species (ROS), a crucial factor triggering diabetic vascular dysfunction. Results The GK rats exhibited marked glucose intolerance as well as insulin resistance. Cardiovascular complications in GK rats were confirmed by elevated arterial blood pressure and reduced VSMC-dependent vasorelaxation. These complications were correlated with high levels of vascular global lysine acetylation. Human VSMC cultures incubated under high glucose conditions displayed elevated ROS levels and increased global lysine acetylation. Inhibition of hyperacetylation by garcinol, a lysine acetyltransferase and p300/CBP association factor (PCAF) inhibitor, reduced high glucose-induced ROS production in VSMC. Conclusion This study provides evidence that vascular hyperacetylation is associated with VSMC dysfunction in advanced T2DM. Understanding lysine acetylation regulation in blood vessels from diabetics may provide insight into the mechanisms of diabetic vascular dysfunction, and opportunities for novel therapeutic approaches to treat diabetic vascular complications.

Neuroprotective Panel of Olive Polyphenols: Mechanisms of Action, Anti-Demyelination, and Anti-Stroke Properties

“…Polyphenols from olive oil and leaves are thought to inhibit mitochondrion ROS and are therefore valuable agents in diabetes therapy [ 151 ]. Endothelial dysfunction is primarily responsible for impaired vasorelaxation and vasodilator factor production in diabetes, but it is closely followed by the development of vascular smooth muscle cell dysfunction [ 152 , 153 ]. The improvement in hyperglycemia with concomitant consumption of olive polyphenols can restore endothelium-dependent vasodilation in experimental models of diabetes [ 152 ].…”

Functions and mechanisms of protein lysine butyrylation (Kbu): Therapeutic implications in human diseases

“…Garcinol, a lysine acetyltransferase inhibitor, has been recently shown to inhibit the p300/CBP association factor (PCAF), reducing ROS overproduction in VSMCs. 93 The above-mentioned studies indicate that metformin affects Kbu levels in T2D patients. Thus, the regulation of Kbu by p300 may provide a direction for future research on the role of metformin in T2D-related Kbu as well as on potential targets for Kbu alterations that would enable more precise diabetes treatment.…”

Oxidative Regulation of Vascular Cav1.2 Channels Triggers Vascular Dysfunction in Hypertension-Related Disorders

“…Various animal models such as type I diabetic rodents induced by streptozotocin (STZ), obese/type II diabetic rodents induced by high-fat diet (HFD), type II diabetic HFD/STZ rodents, type II diabetic Goto-Kakizaki (GK) rats, and type II diabetic C57BL/KsJ-db/db mouse have been developed in diabetes research [ 145 , 146 ]. Systemic vascular resistance (also known as total vascular resistance) and arterial blood pressure are increased in C57BL/KsJ-db/db mice, HFD rats, and GK rats [ 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 ]. Mesenteric arteries of HFD mice, HFD/STZ mice, and diabetic (db/db) mice displayed higher myogenic tone compared to their counterparts [ 58 , 144 , 155 , 156 ].…”

“…Systemic vascular resistance (also known as total vascular resistance) and arterial blood pressure are increased in C57BL/KsJ-db/db mice, HFD rats, and GK rats [ 147 , 148 , 149 , 150 , 151 , 152 , 153 , 154 , 155 ]. Mesenteric arteries of HFD mice, HFD/STZ mice, and diabetic (db/db) mice displayed higher myogenic tone compared to their counterparts [ 58 , 144 , 155 , 156 ]. Similarly, the cerebral arteries of STZ-Sprague Dawley rats, Bio-Breeding Zucker diabetic (BBZDR/Wor) rats, HFD mice, and HFD/STZ mice also exhibit increased myogenic tone [ 144 , 157 , 158 ].…”