Impaired Vasodilation is Associated with Vascular Smooth Muscle Dysfunction and Increased Expression of PCAF Acetyltransferase in a Murine Model of Type 2 Diabetes

The prevalence of T2DM continues to increase at an alarming rate within the United States. In diabetes, blood vessels lose their ability to vasodilate, a major contributor to the development of cardiovascular disease. While several studies have characterized endothelial dysfunction as a key factor contributing to diabetic vascular dysfunction, few studies have focused on examining the pathophysiology of vascular smooth muscle (VSMC) in diabetes. Recent findings from our laboratory and others have suggested that hyperacetylation of proteins may play a role in diabetic complications. We hypothesize that T2DM leads to impaired vasodilation through mechanisms that involve vascular smooth muscle dysfunction and increased P300/CBP‐associated factor (PCAF) expression, an acetyltransferase that adds acetyl groups in the residue lysine of proteins resulting in hyperacetylation. Forty‐eight weeks old male Goto‐Kakizaki (GK) rats, a non‐obese model of T2DM, were utilized in this study. Age‐matched male Wistar rats were used as a non‐T2DM (Control) group. As expected, the T2DM group exhibited elevated blood glucose levels (182 ± 12 vs. 88 ± 3, p<0.001) and elevated glycated hemoglobin levels (HbA1C 8.2 % vs. 5.1% controls) compared with controls. The T2DM group also exhibited an altered lipid profile with increased levels of triglycerides (372.74 ± 12 vs. 48.84 ± 8 mg/dL control, p<0.05), and free fatty acids (1.30 ± 0.2 vs. 0.74 ± 0.1mM control, p<0.001). Cross‐section histology analysis revealed significant structural changes in the aortas of the T2DM group, including disarranged and declined numbers of VSMC, and broken elastin fibers. These morphological alterations may be contributing to the VSMC malfunctioning. We also found the inclusion of numerous foam cells in the medial layer of the aortas. To assess aortic smooth muscle function, cumulative concentration curve for sodium nitroprusside were performed using a wire myography. Aortas from the T2DM group exhibited a marked impairment of endothelium‐independent vasodilation (30% reduction, p<0.05). Our laboratory has previously demonstrated that aortas from diabetic rats are hyperacetylated. Using western blot, we found that PCAF expression was markedly elevated in endothelium‐denuded aortas from the T2DM group (3.5 fold increases vs. control, p<0.05). In conclusion, our results show that VSMC dysfunction plays a crucial role in the impaired vasodilation in diabetes. Increased vascular PCAF and hyperacetylation may be a key mechanism in diabetic vascular dysfunction. Thus, these findings suggest that PCAF could be a potential therapeutic target for treating diabetic patients with vascular complications. To further this investigation, we will be utilizing molecular approaches to downregulate PCAF in the vasculature to confirm the role of PCAF in diabetes‐related vascular disorders. Support or Funding Information In‐house Grant NYIT This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .