Downregulation of Histone Deacetylase 9 (HDAC9) is Associated with Vascular Calcification in Diabetic Mice.

Abstract

Vascular complications, including calcification, are some of the major problems faced by type 2 diabetic (T2DM) patients. In fact, the majority of these diabetic patients will die due to complications of vasculopathy. The current available anti‐diabetic treatment does not prevent the progression of vascular calcification; thus, new therapeutic approaches are urgently needed. Evidence has indicated that HDACs play a central role in the epigenetic mechanisms associated with diabetic complications. Recently, it was identified that a human polymorphism of HDAC9 is linked with acute coronary disease; however, it is still unknown whether HDAC9 is involved in vascular complications in diabetes. We hypothesize that diabetic conditions modulate HDAC9 expression, and this expression is associated with increased markers of vascular calcification. To address our hypothesis, we utilized aortas from fourteen‐week‐old male db/db mice, an experimental model of T2DM, and age‐matched heterozygous nondiabetic (ND) mice (db/m+). Aortas from db/db mice displayed significant increase in osteopontin (OPN) (2.0 fold increase, p<0.01, n=5) and bone morphogenic protein 4 (BMP4) (2.7 fold increase, p<0.05, n=5) compared with the control group, both classical markers of vascular calcification. Most importantly, these findings were correlated with significant downregulation of HDAC9 (1.1 fold reduction vs. control, p<0.05, n=4). Intriguingly, these results differ from previous reports that claim HDAC9 was increased in vascular complications, specifically atherosclerosis and coronary heart disease. Our results suggest that HDAC9 may be regulated differently in diabetic conditions and its downregulation may mediate the progression of vascular diabetic calcification. To further this investigation, we will be utilizing molecular approaches to overexpress HDAC9 in the vasculature to confirm the role of HDAC9 in the diabetic vascular complications.Support or Funding InformationNIH