Postinfarction Gene Therapy Against Transforming Growth Factor-β Signal Modulates Infarct Tissue Dynamics and Attenuates Left Ventricular Remodeling and Heart Failure

May 4, 2005Circulation

Gene therapy targeting a key growth signal after heart attack may change damaged tissue and reduce heart enlargement and failure

AI simplified

Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Survival rates improved to 96% in mice treated with TGF-beta signaling inhibition after myocardial infarction.

Inhibition of TGF-beta signaling reduced fibrous tissue formation in the heart post-myocardial infarction.
Ventricular dilatation was significantly less in treated mice compared to controls four weeks after injury.
Treated mice exhibited improved heart function, despite no difference in the size of myocardial infarction.
A higher presence of alpha-smooth muscle actin-positive cells in treated mice may support better infarct contraction.
Fewer myofibroblast deaths were observed in the treatment group, indicating potential protective effects on heart tissue.

AI simplified

BACKGROUND: Fibrosis and progressive failure are prominent pathophysiological features of hearts after myocardial infarction (MI). We examined the effects of inhibiting transforming growth factor-beta (TGF-beta) signaling on post-MI cardiac fibrosis and ventricular remodeling and function.

METHODS AND RESULTS: MI was induced in mice by left coronary artery ligation. An adenovirus harboring soluble TGF-beta type II receptor (Ad.CAG-sTbetaRII), a competitive inhibitor of TGF-beta, was then injected into the hindlimb muscles on day 3 after MI (control, Ad.CAG-LacZ). Post-MI survival was significantly improved among sTbetaRII-treated mice (96% versus control at 71%), which also showed a significant attenuation of ventricular dilatation and improved function 4 weeks after MI. At the same time, histological analysis showed reduced fibrous tissue formation. Although MI size did not differ in the 2 groups, MI thickness was greater and circumference was smaller in the sTbetaRII-treated group; within the infarcted area, alpha-smooth muscle actin-positive cells were abundant, which might have contributed to infarct contraction. Apoptosis among myofibroblasts in granulation tissue during the subacute stage (10 days after MI) was less frequent in the sTbetaRII-treated group, and sTbetaRII directly inhibited Fas-induced apoptosis in cultured myofibroblasts. Finally, treatment of MI-bearing mice with sTbetaRII was ineffective if started during the chronic stage (4 weeks after MI).

CONCLUSIONS: Postinfarction gene therapy aimed at suppressing TGF-beta signaling mitigates cardiac remodeling by affecting cardiac fibrosis and infarct tissue dynamics (apoptosis inhibition and infarct contraction). This suggests that such therapy may represent a new approach to the treatment of post-MI heart failure, applicable during the subacute stage.

Full Text

Full text is available at the source.

View full text ↗

Postinfarction Gene Therapy Against Transforming Growth Factor-β Signal Modulates Infarct Tissue Dynamics and Attenuates Left Ventricular Remodeling and Heart Failure

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the longevity & aging brief