Chronic AT ₁ Blockade Stimulates Extracellular Collagen Type I Degradation and Reverses Myocardial Fibrosis in Spontaneously Hypertensive Rats

Abstract

Abstract-It has been suggested that left ventricular fibrosis in spontaneously hypertensive rats (SHR) is the result of both exaggerated collagen synthesis and insufficient collagen degradation. We have shown previously that chronic treatment with the angiotensin II type 1 receptor antagonist losartan results in diminished synthesis of collagen type I molecules and reversal of myocardial fibrosis in SHR. This study was designed to investigate whether losartan also affects the extracellular degradation of collagen type I fibers in the left ventricle of SHR. 4 -9 Chronic blockade of the angiotensin II type 1 (AT 1 ) receptor with losartan resulted in the normalization of collagen synthesis and reversal of left ventricular fibrosis in SHR, which suggests a role for angiotensin II in increased collagen synthesis in that model. 6 The excess of ventricular collagen in patients with hypertensive LVH may be a result of both exaggerated collagen synthesis and inadequate collagen degradation. 10,11 The ratelimiting step in the extracellular degradation of collagen is the catalytic cleavage by interstitial matrix metalloproteinases (MMPs). 12 Nine MMPs have been identified, cloned, and sequenced, and these are divided into 3 groups (collagenase, stromelysin, and gelatinase) that are based broadly on substrate preferences. Interstitial collagenase (MMP-1) accounts for the degradation of up to 40% of newly synthesized collagen type I and type III in different tissues. 13 The MMP activity is regulated by a family of naturally occurring tissue inhibitors of metalloproteinases (TIMPs). 12,14 Four members of this family have been identified: TIMP-1, TIMP-2, TIMP-3, and TIMP-4. Unlike the other TIMPs, TIMP-1 is synthesized by most types of connective tissue cells, acts against all members of the MMPs family of enzymes, and is

Involvement of Angiotensin II Type 1 and 2 Receptors in Gelatinase Regulation in Human Carotid Atheroma <i>in vitro </i>

“…TIMP expression [45][46][47] . TIMP-1 expression was virtually abolished with additional inclusion of an ATR2 blocker.…”

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

“…Large clinical trials evaluating the blockade of RAS with ACE inhibitors or angiotensin receptor blockers have demonstrated an ability to prevent progression and to induce regression of cardiac hypertrophy improving ventricular performance (36,37). Indeed, the chronic administration of an AT1 receptor antagonist (Losartan) resulted in the reversal of fibrosis, inhibition of the post-transcriptional synthesis of procollagen type I, inhibition of tissue inhibitor of metalloproteinase-1 expression and stimulation of collagenase activity in the left ventricle of spontaneously hypertensive adult rats (38), thereby reducing the significant and independent cardiovascular risk conferred by cardiac remodeling.…”

Losartan-Dependent Regression of Myocardial Fibrosis Is Associated With Reduction of Left Ventricular Chamber Stiffness in Hypertensive Patients

“…It has been proposed that the excess of myocardial collagen seen in hypertension is the result of both increased collagen synthesis and decreased collagen degradation. 2 Recent experimental 3,4 and clinical 5 findings suggest that the interaction of angiotensin II with its type 1 (AT 1 ) receptors plays a critical role in alterations of collagen type I metabolism and development of myocardial fibrosis in arterial hypertension.…”