Abstract

Perspectives on whether the functions of MAS, a G protein-coupled receptor, are beneficial or deleterious in the heart remain controversial. MAS gene knockout reduces coronary vasodilatation leading to ischemic injury. G protein signaling activated by MAS has been implicated in progression of adaptive cardiac hypertrophy to heart failure and fibrosis. In the present study, we observed increased expression of MAS, connective tissue growth factor (CTGF) and collagen genes in failing (HF) human heart samples when compared to non-failing (NF). Expression levels of MAS are correlated with CTGF in HF and NF leading to our hypothesis that MAS controls CTGF production and the ensuing expression of collagen genes. In support of this hypothesis we show that the non-peptide MAS agonist AR234960 increases both mRNA and protein levels of CTGF via ERK1/2 signaling in HEK293-MAS cells and adult human cardiac fibroblasts. MAS-mediated CTGF expression can be specifically blocked by MAS inverse agonist AR244555 and also by MEK1 inhibition. Expression of CTGF gene was essential for MAS-mediated up-regulation of different collagen subtype genes in HEK293-MAS cells and human cardiac fibroblasts. Knockdown of CTGF by RNAi disrupted collagen gene regulation by the MAS-agonist. Our data indicate that CTGF mediates the profibrotic effects of MAS in cardiac fibroblasts. Blocking MAS-CTGF-collagen pathway should be considered for pharmacological intervention for HF.

Highlights

  • Heart failure (HF) in humans, characterized by a heart unable to pump blood to meet the body’s needs, is one of the most common causes of mortality [1]

  • Expression of MAS is correlated with connective tissue growth factor (CTGF) and fibrosis in human heart samples We compared steady-state expression of MAS transcripts in the frozen human heart tissue left ventricular (LV) wall, categorized as failing (HF) and non-failing (NF) samples

  • To identify the specific signaling pathway downstream of the G protein that is involved in CTGF expression, we studied activation of kinases, ERK1/2, p38MAPK, JNK, JAK2, PKC-γ and the transcription modulator STAT3 in HEK293-MAS cells as well as in human cardiac fibroblasts (HCF) cells (Data not shown)

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Summary

Introduction

Heart failure (HF) in humans, characterized by a heart unable to pump blood to meet the body’s needs, is one of the most common causes of mortality [1]. Three different GPCRs, AT1R, AT2R and MAS mediate RAAS effects on cells [4,12] Of these AngII-activation of AT1R has been shown to increase collagen production in cardiac fibroblasts and AngII-activation of AT2R may inhibit this process [4]. To selectively activate MAS in this study, we used the MAS-specific non-peptide agonist AR234960 [16,18] and demonstrated that CTGF expression is activated which in turn regulates collagen expression. Both effects are blocked by the MAS-specific inverse agonist AR244555

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