Abstract 089: Role of Nox5 in Systemic Vascular Dysfunction in Ischemic Heart Disease

Abstract

Patients with coronary microvascular dysfunction (CMD), a potential cause of heart ischemia, have systemic vascular dysfunction, characterized by increased vascular contraction to ET-1 and a thromboxane A2 analogue (U46619). Nox5 regulates vascular contraction and is involved in cardiovascular diseases. In our study, we questioned whether Nox5 plays a role in systemic vascular dysfunction in heart ischemia. As Nox5 expression has been described in the cardiovascular system of rabbits, a model of ischaemic cardiomyopathy (IC) was used. Coronary artery ligation was performed in Male New Zealand White rabbits. After 8 weeks, skin and mesenteric arteries were isolated and vascular function assessed by wire myography. Vascular contraction to NA (EMax %KCl: 122±4 vs sham 97±3.7) and U46619 (EMax %KCl: 82±3 vs sham 67±4) were exacerbated in skin arteries from IC (p<0.05); an effect blocked by tiron (antioxidant, 10 μM) and melittin (nox5 inhibitor, 0.1 μM). In mesenteric arteries from IC animals, NA (EMax %KCl: 108±3 vs sham 98±7) and ET-1 (EMax %KCl: 103±3 vs sham 81±4) induced contraction were increased in a Nox5-ROS-dependent manner (p<0.05). No differences were observed in mRNA levels of Cav1.2 and IP3R Ca 2+ channels, but an increase in RyR was observed (2^-ddCT: 1.67±0.15 vs sham 0.98±0.08) in VSMCs isolated from IC animals. Peroxiredoxin (Prdx), antioxidant, mRNA was increased in IC (2^-ddCT: 1.95±0.4 vs sham 0.88±0.1, p<0.05). Conoidin A, an inhibitor of Prdx oxidation, reduced vascular contraction to NA in arteries from IC animals (EMax %KCl: 95±4, p<0.05). In subjects with CMD, we assessed total number of microparticles (MP) as biomarkers of vascular dysfunction. MPs were increased in CMD subjects (x10 11 /mL: 4.8±0.6 vs control 1.75±0.2), where Nox5 expression was also increased (AU: 0.11±0.02 vs control MP 0.03±0.006) (p<0.05). In separate studies, we exposed WT control arteries to MPs from WT and Nox5-expressing mice before assessing contraction. MPs from Nox5 mice increased contraction to a higher level of that observed with MPs from WT mice (EMax %KCl: 106±2 vs WT 96±2, p<0.05). In our study, we identify Nox5 as a regulator of systemic vascular dysfunction in ischemic heart diseases, through mechanisms that may involve ROS, Prdx oxidation and MPs.