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 (1,500 ng/kg per minute) for 7 days; 40 male mice (6 weeks old) were randomly assigned to 4 groups for treatment: mice with angiotensin II or vehicle infusion were given hydralazine in drinking water (250 mg/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.

Differential effect of angiotensin II and blood pressure on hippocampal inflammation in mice

“…At the same time, our results on blood pressure complement the findings of Marvar and colleagues who used a similar approach with hydralazine to demonstrate that the pressor effects of Ang II are critical for the activation of circulating T lymphocytes and the expression of vascular inflammation in mice [31]. Interestingly, there is also evidence that hydralazine attenuates cardiac fibrosis and inflammation induced by pressive Ang II in mice, suggesting that blood pressure is also a key contributor to the expression of inflammation in other end organs affected by hypertension besides the brain [38].…”

Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

“…Hydralazine was chosen based on its antihypertensive properties of lowering blood pressure in a dose-dependent manner without acting on AngII receptors. 24,25 RAS upregulation was demonstrated in the animals that received AngII+hydralazine, as evidenced by a significant elevation in serum aldosterone, which is a downstream mediator and marker of RAS activation. Our primary observation using this model was that the addition of hydralazine to AngII resulted in normalization of the blood pressure and inhibition of the fibrosis that is normally seen in animals receiving AngII.…”

“…Our findings are in keeping with other studies that have suggested that the effects of AngII on fibrosis are blood pressure dependent. 24,25,39 Some reports have even suggested that blood pressure can affect the migration of fibrocytes (CD45 + /SMA + ) into the myocardium, but these reports did not elucidate a definitive mechanism. 25 In contrast, transgenic mice that overexpress the AT1a receptor and develop hypertrophy and fibrosis do so without developing hypertension, emphasizing the multifactorial pathways capable of promoting extracellular matrix deposition and fibrosis.…”

“…24,25,39 Some reports have even suggested that blood pressure can affect the migration of fibrocytes (CD45 + /SMA + ) into the myocardium, but these reports did not elucidate a definitive mechanism. 25 In contrast, transgenic mice that overexpress the AT1a receptor and develop hypertrophy and fibrosis do so without developing hypertension, emphasizing the multifactorial pathways capable of promoting extracellular matrix deposition and fibrosis. 40 However, these findings were based on transgenic mice that had abnormal RAS regulation based on overexpression of only the AT1 receptor.…”

Drug Treatment of Hypertension: Focus on Vascular Health

“…Angiotensin II acts through two receptors -AT1 and AT2, with AT1 activation playing a major role in the production of ECM proteins and vascular fibrosis 2,[95][96][97][98] . Whilst the precise mechanisms involved in angiotensin II related vascular fibrosis remain to be fully defined, increased activity of TGF-β-1, galectin-3, p38 MAPK and MMPs/TIMPs may all contribute.…”