Blockade of PAR‐1 Signaling Attenuates Cardiac Hypertrophy and Fibrosis in Renin‐Overexpressing Hypertensive Mice

Abstract

Background Although PAR‐1 (protease‐activated receptor‐1) exerts important functions in the pathophysiology of the cardiovascular system, the role of PAR ‐1 signaling in heart failure development remains largely unknown. We tested the hypothesis that PAR ‐1 signaling inhibition has protective effects on the progression of cardiac remodeling induced by chronic renin–angiotensin system activation using renin‐overexpressing hypertensive (Ren‐Tg) mice. Methods and Results We treated 12‐ to 16‐week‐old male wild‐type ( WT ) mice and Ren‐Tg mice with continuous subcutaneous infusion of the PAR ‐1 antagonist SCH 79797 or vehicle for 4 weeks. The thicknesses of interventricular septum and the left ventricular posterior wall were greater in Ren‐Tg mice than in WT mice, and SCH 79797 treatment significantly decreased these thicknesses in Ren‐Tg mice. The cardiac fibrosis area and monocyte/macrophage deposition were greater in Ren‐Tg mice than in WT mice, and both conditions were attenuated by SCH 79797 treatment. Cardiac mRNA expression levels of PAR ‐1, TNF‐α (tumor necrosis factor‐α), TGF‐β1 (transforming growth factor‐β1), and COL3A1 (collagen type 3 α1 chain) and the ratio of β‐myosin heavy chain (β‐ MHC ) to α‐ MHC were all greater in Ren‐Tg mice than in WT mice; SCH 79797 treatment attenuated these increases in Ren‐Tg mice. Prothrombin fragment 1+2 concentration and factor Xa in plasma were greater in Ren‐Tg mice than in WT mice, and both conditions were unaffected by SCH 79797 treatment. In isolated cardiac fibroblasts, both thrombin and factor Xa enhanced ERK1/2 (extracellular signal‐regulated kinase 1/2) phosphorylation, and SCH 79797 pretreatment abolished this enhancement. Furthermore, gene expression of PAR ‐1, TGF ‐β1, and COL 3A1 were enhanced by factor Xa, and all were inhibited by SCH 79797. Conclusions The results indicate that PAR ‐1 signaling is involved in cardiac remodeling induced by renin–angiotensin system activation, which may provide a novel therapeutic target for heart failure.

Thrombin Inhibition Prevents Endothelial Dysfunction and Reverses 20-HETE Overproduction without Affecting Blood Pressure in Angiotensin II-Induced Hypertension in Mice

“…It has been previously reported that activators or blockers of thrombin-activated PAR-1 evoke a decrease and increase in blood pressure in healthy animals, respectively [28], whereas the blockade of PAR-1 in renin-overexpressing mice reduces hypertension [29]. Moreover, PAR-1 receptors in the vasculature are known to contribute to endotheliummediated vasodilatation and smooth muscle cell (SMC)-mediated vasoconstriction [30].…”

Cardioprotection by direct factor Xa inhibition in angiotensin II overexpression

“…PAR-1-knockout mice treated with a subpressor dose of Ang II for 4 weeks failed to cause vascular remodeling of the aorta but did induce cardiac hypertrophy, in contrast to the effect on wild-type mice, indicating that PAR-1 plays a significant role in "vascular" remodeling induced by Ang II without raising blood pressure. Narita et al also previously demonstrated cardioprotective effects of PAR-1 inhibition by SCH79797, a PAR-1 antagonist, on cardiac hypertrophy and fibrosis in Ren-2 mice [7]. They also showed that the FXa-induced enhancement of hypertrophic signaling in isolated cardiac fibroblasts was abolished by SCH79797, indicating that both PAR-1 and PAR-2 are activated in association with FXa in Ren-2 mice.…”

Targeting GPCRs to treat cardiac fibrosis

“…Activation of protease-activated receptor-1 (PAR1), which couples to Gq/11, Gi/o, and G12/13, elevates the level of profibrotic gene expression in rat cardiac fibroblasts, leading to myofibroblast activation and increasing collagen synthesis by 60% ( 48 ). Conversely, inhibiting PAR1 with SCH79797 attenuates cardiac fibrosis and hypertrophy in the renin-overexpressing induced hypertensive mice model ( 16 ). However, PAR1 is highly expressed in platelets, and its antagonist is used for antiplatelet therapy ( 49 ).…”