Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling

Abstract

AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-β serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-β signalling, protected mice against progressive ventricular dysfunction, and significantly reduced the mortality after experimental MI (myocardial infarction). In the present study, we investigated the role of fibulin-2 in AngII-induced TGF-β signalling and subsequent cardiac hypertrophy. We performed chronic subcutaneous infusion of AngII in fibulin-2 null (Fbln2−/− ), heterozygous (Fbln2+/− ) and WT (wild-type) mice by a mini-osmotic pump. After 4 weeks of subpressor dosage of AngII infusion (0.2 μg/kg of body weight per min), WT mice developed significant hypertrophy, whereas the Fbln2−/− showed no response. In WT, AngII treatment significantly up-regulated mRNAs for fibulin-2, ANP (atrial natriuretic peptide), TGF-β1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-β-downstream signalling markers, Smad2, TAK1 (TGF-β-activated kinase 1) and p38 MAPK (mitogen-activated protein kinase), which were all unchanged in AngII-treated Fbln2−/− mice. The Fbln2+/− mice consistently displayed AngII-induced effects intermediate between WT and Fbln2−/− . Pressor dosage of AngII (2 mg/kg of body weight per min) induced significant fibrosis in WT but not in Fbln2−/− mice with comparable hypertension and hypertrophy in both groups. Isolated CFs (cardiac fibroblasts) were treated with AngII, in which direct AngII effects and TGF-β-mediated autocrine effects was observed in WT. The latter effects were totally abolished in Fbln2−/− cells, suggesting that fibulin-2 is essential for AngII-induced TGF-β activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-β-mediated cardiac hypertrophy via enhanced TGF-β activation and suggest that fibulin-2 is a potential therapeutic target to inhibit AngII-induced cardiac remodelling.

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…Fibulin-2 is a likely matricellular protein that is upregulated by ANG II and is required in turn for upregulation of TGF-␤. Knockout of fibulin-2 prevents ANG II-induced cardiac fibrosis at subpressor and pressor doses, but cardiac hypertrophy only at subpressor doses of ANG II (487,1247). Recently, evidence was presented that ANG II induces cardiac hypertrophy in vivo through the release of exosomes from cardiac fibroblasts that are enriched in passenger strand miR-21*, causing the downregulation of sorbin and SH3 domain-containing protein 2 (SORBS2) and PDZ and LIM domain 5 (PDLIM5) in cardiac myocytes (52).…”

“…Supraphysiological levels of ANG II (Ն400 ng·kg Ϫ1 ·min Ϫ1 ) are associated with endothelial dysfunction and vascular injury in the heart concomitant with inflammation and the recruitment of macrophages that drive fibrosis (325,995). Surprisingly, the influence of a subpressor dose of ANG II (~200 ng·kg Ϫ1 ·min Ϫ1 ) on cardiac structure has been less well studied, but reported to induce both cardiac myocyte hypertrophy and increased interstitial fibrosis or collagen type I (Col I) deposition (67,862,1247). It was recently proposed that chronic infusion of the mouse with low-dose ANG II may serve as a model for studying the pathogenesis of heart failure with preserved ejection fraction (HFpEF), which is characterized by concentric cardiac hypertrophy and diastolic dysfunction due in part to increased interstitial fibrosis (862).…”

MicroRNA as a Therapeutic Target in Cardiac Remodeling

“…A study found that there is an inverse correlation between the expression of miR-1 in myocardial tissue and FABP3 level in circulation [10]. Another research group found that miR-1 inhibits fibulin-2 (Fbln2) expression and thereby it abolishes activation of TGF β signaling and extracellular matrix remodeling in hypertrophic heart [11, 12]. MiR-133 is one of the abundantly expressed antihypertrophic miR in both animal and human myocardial tissues.…”

Proteases in cardiometabolic diseases: Pathophysiology, molecular mechanisms and clinical applications

“…The role of MMPs has been extensively studied in hypertensive heart disease due to the involvement of ECM in cardiac remodeling that is commonly associated with the hypertensive heart. Elevated MMPs expression levels have been documented in hearts from different models of hypertensive animal, including angiotensin II-induced hypertension [148], pulmonary hypertension [149], renovascular hypertension [150], spontaneously hypertensive rats [151], volume overload [152] and pressure overload-induced hypertension [153]. Studies by using transgenic models further declare the contributions of MMP/TIMP in hypertensive heart disease.…”