Pressure-Independent Effects of Angiotensin II on Hypertensive Myocardial Fibrosis

Abstract

Abstract-Angiotensin II (Ang II) is implicated in the proinflammatory process in various disease situations. Thus, we sought to determine the role of Ang II in early inflammation-induced fibrosis of pressure-overloaded (PO) hearts. PO was induced by suprarenal aortic constriction (AC) at day 0 in male Wistar rats, and they were orally administered 0.1 mg/kg per day candesartan every day from day Ϫ7. This was the maximum dose of candesartan that did not change arterial pressure in hypertensive rats with AC (AC rats). In AC rats, cardiac angiotensin-converting enzyme (ACE) activity was transiently enhanced after day 1 and peaked at day 3, declining to lower levels by day 14, whereas serum ACE activity was not changed. In AC rats, PO induced early fibroinflammatory changes (monocyte chemoattractant factor [MCP]-1 and transforming growth factor [TGF]-␤ expression, perivascular macrophage accumulation, and fibroblast proliferation), and thereafter, left ventricular hypertrophy developed, featuring myocyte hypertrophy, intramyocardial arterial wall thickening, and perivascular and interstitial fibroses. Candesartan suppressed the induction of MCP-1 and TGF-␤ and reduced macrophage accumulation and fibroblast proliferation in PO hearts. Candesartan significantly prevented perivascular and interstitial fibrosis. However, candesartan did not affect myocyte hypertrophy and arterial wall thickening. In conclusion, a subdepressor dose of candesartan prevented the MCP-1-mediated inflammatory process and reactive myocardial fibrosis in PO hearts. Ang II might play a key role in reactive fibrosis in hypertensive hearts, independent of arterial pressure changes.

Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women

“…9,10 AC-induced inflammatory changes result in myocardial fibrosis in the early phase and diastolic dysfunction in the later phase. 9,11,12,19 In this study, AC induced cardiac remodeling and diastolic dysfunction associated with inflammatory changes and superoxide generation in control female rats. A growing body of evidence implicates vascular inflammation in cardiovascular diseases in postmenopausal hypertensive women.…”

“…18 Immunohistostaining for monocytes/macrophages was performed using an antibody against ED1 (Chemicon International, Temecula, CA, USA) and a commercially available detection system (DAKO, Glostrup, Denmark). 9,19 The number of macrophages were counted at Â200 magnification in four independent, whole cross-sections in each rat.…”

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

“…38,39 In contrast, the circulating and autocrine/paracrine humoral factors, such as angiotensin II, TGF-b and MCP-1, have been implicated in hypertensive myocardial fibrosis. 23,25,[40][41][42] Further research is necessary, to determine the mechanism by which simvastatin induces the different effects between myocyte hypertrophy and myocardial fibrosis in this model.…”

“…23,24 Macrophages labeled with an antibody for ED-1 (Chemicon International, Temecula, CA, USA) were counted at Â200 magnification in three independent entire cross-sections of each animal. 25 …”

Sympathetic drive stimulating diastolic dysfunction?

“…3 Angiotensin II causes pressure-independent myofibrosis, hypertrophy, and impaired myocardial relaxation. 4 Under ischemic conditions, increased circulating levels of angiotensin II have been associated with worsening diastolic function 5 Aldosterone is increased in animal models with pressure overload states. Aldosterone stimulates mineralocorticoid receptors, phosphokinase C, and reactive oxygen species-dependent activation of the mitogen/ extracellular signal-regulated kinase MEK/ERK pathway.…”