Abstract P338: Aging and Inhibition of Nox1/4 Modulate Perivascular Inflammation in Spontaneous Hypertension

Abstract

Introduction: Hypertension is associated with enhanced oxidative stress and perivascular inflammation. Although, that aging and oxidative stress are major factors in the development of hypertension their effect on perivascular inflammation remains unclear. Methods: Using flow cytometry we studied leukocytes infiltrating perivascular adipose tissue (PVAT) in 1-, 3-, 6- and 12-month-old SHR (Spontaneously Hypertensive Rats) and normotensive WKY (Wistar-Kyoto) rats. Additionally, 1-month-old rats were treated with GKT137831 (60mg/kg) or ML171 (NOX1/4 and NOX1 inhibitor, respectively) for 4 weeks. Blood pressure (PB) was measured by the tail cuff. Results: Aging in SHRs was associated with elevation of BP (139±4 vs 180±4 vs 202±2 vs 208±2 mmHg; 1 vs 3 vs 6 vs 12-month-old, respectively) when this effect was not seen in WKY rats. While the total number of leukocytes infiltrating PVAT were comparable between 1-month-old WKY and SHR (p=0.8) aging escalated their numbers only in SHRs (2096±164 vs 1994±296 vs 2311±470 vs 3255±408 cell/mg; p int <0.001). Similar effect was observed among NK cells (p int <0.001) and macrophages (p int <0.001). Moreover, spontaneous hypertension was associated with 2-fold elevation of T cells residing in PVAT in comparison to WKY, however, aging did not affect their number in both groups. While the age-related increase of Nox4 mRNA was observed in both groups, this increase was more dynamic in SHRs, (p int <0.05). Furthermore, 5-, 6- and 9-fold induction of Nox1 mRNA was observed in the vessels of 3-, 6- and 12-months-old SHRs, respectively (p<0.01). GKT137831 treatment significantly increased BP (p<0.01, 2way ANOVA) in both WKY and SHR (150±2 vs 164±3 mmHg, 198±4 vs 209±3 mmHg, respectively). This was accompanied by elevation of the total number of leukocytes (988±180 vs 1471±88 cell/mg, 1487±945 vs 1878±164 cell/mg) and macrophages (107±14 vs. 153±14 cell/mg, 228±26 vs. 298±42) in PVAT of WKYs and SHRs treated with GKT137831. On the contrary, ML171 treatment protected against increased accumulation of CD45+ cells in PVAT, without affecting BP. Conclusions: Aging in spontaneous hypertension is associated with elevation of BP and aggravation of perivascular inflammation which are hastened after NOX1/4 inhibitor treatment.