Abstract 083: Macrophages Dictate the Progression and Manifestation of Hypertensive Heart Disease in Rat

Abstract

Introduction: Inflammation has been implicated in the initiation, progression and manifestation of hypertension. However, the role of macrophages in hypertension-induced LV remodeling has yet to be determined. Hypothesis: We assessed the hypothesis that macrophages play a significant role in the initiation and progression of hypertension-induced LV remodeling. Methods and Results: Hypertension was induced in male Sabra salt-sensitive (SBH/y) rats with high salt diet (8%NaCl) over 6 weeks. Hypertensive SBH/y developed LV hypertrophy, hyper-contractility and a higher LV ejection fraction (EF). Notably, the number of macrophages, particularly cardiac macrophages was significantly greater in hypertensive SBH/y than in controls. Macrophage depletion was induced after induction of hypertension by intravenous administration of clodronate liposomes at 3-day intervals over 4 weeks (n=9) and was validated by FACS analysis and ED1 (CD68) staining of heart sections. Control hypertensive rats (n=9) were treated with PBS liposomes. Surprisingly, macrophage depletion attenuate the progression of hypertension in the clodronate-treated group (from 177±2 to 179±2 mmHg) compared with controls (from 179±2 to 184 ± 5mmHg; p=0.01).Serial echocardiography studies before and 30 days after initiation of macrophage depletion or control showed that LV systolic diameter and volume were smaller; anterior wall thickening, fractional shortening and EF were higher in the macrophage-depletion group (p<0.05). LV strain and strain rate were significantly higher in the macrophage depletion group (p=0.04). Furthermore, 1 month after BP elevation, the expression of miR-31, which has been implicated in the pathogenesis of cardiac hypertrophy, was decreased (4.6-fold) in the macrophage-depleted hearts compared to controls, suggesting that macrophages control miR-31 expression in LV hypertrophy. Conclusion: Our findings suggest a significant role of macrophages in the initiation and progression of salt-sensitive hypertension and the related heart disease. Targeting macrophages, therefore, could be a potential therapeutic target for the treatment of hypertension and prevention of LV remodeling and dysfunction.