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

Abstract

Background— Fibrosis and progressive failure are prominent pathophysiological features of hearts after myocardial infarction (MI). We examined the effects of inhibiting transforming growth factor-β (TGF-β) 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-β type II receptor (Ad.CAG-sTβRII), a competitive inhibitor of TGF-β, was then injected into the hindlimb muscles on day 3 after MI (control, Ad.CAG-LacZ). Post-MI survival was significantly improved among sTβRII-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 sTβRII-treated group; within the infarcted area, α-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 sTβRII-treated group, and sTβRII directly inhibited Fas-induced apoptosis in cultured myofibroblasts. Finally, treatment of MI-bearing mice with sTβRII was ineffective if started during the chronic stage (4 weeks after MI). Conclusions— Postinfarction gene therapy aimed at suppressing TGF-β 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.

Angiotensin (1−7) prevent heart dysfunction and left ventricular remodeling caused by renal dysfunction in 5/6 nephrectomy mice

“…Recently, Peterson 14 showed that both cardiac hypertrophy and fibrosis in heart failure are characterized by an elevated level of circulating TGF-b and Fedulov et al 15 showed a strong positive correlation between serum TGF-b and cardiac fibrosis. Okada 16 has also recently shown that gene therapy directed against TGF-b attenuates left ventricular remodeling and heart failure, after a myocardial infarction, in a time-dependent manner. Angiotensin (1À7) prevent heart dysfunction and left ventricular remodeling Y Li et al…”

The immune system and cardiac repair

“…Two recent studies showed that inhibition of TGF-β signaling by injection of an adenovirus harboring soluble TGF-β type II receptor in the hindlimb muscles resulted in attenuated left ventricular remodeling by modulating cardiac fibrosis [318], [319]. However, early TGF-β inhibition significantly increased mortality and exacerbated left ventricular dilation enhancing cytokine synthesis, suggesting that during the phase of resolution of the inflammatory response, TGF-β signaling plays an important role in suppression of inflammatory mediator synthesis [318].…”

The role of transforming growth factor (TGF)-β in the infarcted myocardium

“…In a model of non-reperfused infarction, TGF-β inhibition through administration of a neutralizing antibody had detrimental effects, accentuating chamber dilation, increasing myocardial MMP expression, and reducing collagen synthesis (84). Two independent investigations inhibiting TGF-β by using gene transfer of the extracellular domain of TβRII suggested that TGF-β may play a key role in fibrosis of the infarcted heart (63,85). TGF-β inhibition after the inflammatory phase of cardiac repair attenuated deposition of fibrous tissue in the infarcted region (85).…”