Loss of fibulin-2 protects against progressive ventricular dysfunction after myocardial infarction

Abstract

Remodeling of the cardiac extracellular matrix (ECM) is an integral part of wound healing and ventricular adaptation after myocardial infarction (MI), but the underlying mechanisms remain incompletely understood. Fibulin-2 is an ECM protein upregulated during cardiac development and skin wound healing, yet mice lacking fibulin-2 do not display any identifiable phenotypic abnormalities. To investigate the effects of fibulin-2 deficiency on ECM remodeling after MI, we induced experimental MI by permanent coronary artery ligation in both fibulin-2 null and wild-type mice. Fibulin-2 expression was up-regulated at the infarct border zone of the wild-type mice. Acute myocardial tissue responses after MI, including inflammatory cell infiltration and ECM protein synthesis and deposition in the infarct border zone, were markedly attenuated in the fibulin-2 null mice. However, the fibulin-2 null mice had significantly better survival rate after MI compared to the wild-type mice as a result of less frequent cardiac rupture and preserved left ventricular function. Up-regulation of TGF-β signaling and ECM remodeling after MI were attenuated in both ischemic and non-ischemic myocardium of the fibulin-2 null mice compared to the wild type counterparts. Increase in TGF-β signaling in response to angiotensin II was also lessened in cardiac fibroblasts isolated from the fibulin-2 null mice. The studies provide the first evidence that absence of fibulin-2 results in decreased up-regulation of TGF-β signaling after MI and protects against ventricular dysfunction, suggesting that fibulin-2 may be a potential therapeutic target for attenuating the progression of ventricular remodeling.

Enhanced Bioactive Myocardial Transforming Growth Factor-β in Advanced Human Heart Failure

“…We recently showed that the ECM protein fibulin-2 modulated TGF-β activation and ventricular remodeling after myocardial infarction 13 and continuous Ang II infusion 14 in mice.…”

“…22 In human DCM, in contrast to the present findings of no significant increase in TGF-β mRNA or protein abundance in severely failing hearts, 1 previous study reported increased TGF-β1 and TGF-β2 expression based on qRT-PCR. 6 That Fibulin-2 null mice had significantly better survival after myocardial infarction than wild-type mice due to preserved LV function in conjunction with attenuated TGF-β activation, 13 and failed to show Ang II-induced myocardial hypertrophy and fibrosis secondary to attenuation of TGF-β activation. 14 Both studies suggested that upregulation of fibulin-2 and subsequent TGF-β activation are critical processes in the pathogenesis of ventricular remodeling in the mouse model and that the decrease in fibulin-2 is likely to prevent progression of ventricular remodeling and heart failure.…”

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

“…The expression of fibulin-2 is up-regulated during tissue remodelling, such as in skin wounds and vascular lesions [26,27]. Mice lacking fibulin-2 do not show any obvious phenotypic anomalies [28], but our recent studies revealed that loss of fibulin-2 in mice significantly improved the survival rate after experimental MI through attenuating progressive ventricular dysfunction accompanied by reduced TGF- β activation compared with WT (wild-type) mice [29]. Thus we hypothesized that fibulin-2 positively modulates TGF- β activation during cardiac remodelling.…”

FBLN2 (fibulin 2)

“…Fibulin-2 is also upregulated in transformed cells that migrate into the extracellular matrix of cardiac valves and aortic arch vessels and authors suggest that fibulin-2 is also required for the correct formation of coronary arteries and veins in postnatal life (Tsuda et al, 2001). However, although mice lacking fibulin-2 do not show any obvious phenotypic anomalies (Sicot et al, 2008), loss of fibulin-2 significantly improved the survival rate after experimental myocardial infarction through attenuating progressive ventricular dysfunction accompanied by reduced activation of the TGFβ-dependent pathway (Tsuda et al, 2012). The modulation of this signalling pathway by fibulin-2 in heart homeostasis has also been described in an angiotensin II-induced heart hypertrophy model (Zhang et al, 2014).…”