Angiotensin II Infusion–Induced Inflammation, Monocytic Fibroblast Precursor Infiltration, and Cardiac Fibrosis are Pressure Dependent

Abstract

The activated renin-angiotensin-aldosterone system increases blood pressure and intracellular signals, thus leading to cardiac fibrosis. Whether increased blood pressure or angiotensin II-activated signaling is responsible for elevated angiotensin II-induced cardiac remodeling is unknown. Here, we aimed to determine whether lowering blood pressure with hydralazine might prevent inflammation and cardiac fibrosis in response to angiotensin II. We used the C57/BL6 mouse model of angiotensin II infusion (1,500ng/kg per minute) for 7days; 40 male mice (6weeks old) were randomly assigned to 4 groups for treatment: mice with angiotensin II or vehicle infusion were given hydralazine in drinking water (250mg/l per day). Heart sections were stained with hematoxylin and eosin and Masson trichrome and examined by immunohistostaining. The levels of proinflammatory cytokines were measured by real-time PCR and western blot analysis. The blood pressure of the control group began to increase on day 4 of angiotensin II infusion, and hydralazine treatment prevented angiotensin II-induced hypertension. Compared with the control, hydralazine treatment to lower blood pressure blocked angiotensin II-induced fibrosis and reduced Mac-2(+) inflammatory cell infiltration and proinflammatory cytokine expression. The accumulation of blood-borne CD45(+) cells and α-smooth muscle actin-positive myofibroblasts was also significantly reduced. Our results indicate that elevated blood pressure is essential for inflammatory cell infiltration and myofibroblast formation, which contribute to angiotensin II infusion-induced cardiac fibrosis. Hydralazine treatment attenuates cardiac fibrosis in response to angiotensin II. Lowering pressure could be an effective therapeutic target for cardiac fibrosis.