Significance of Thymosin β4 and Implication of PINCH-1-ILK-α-Parvin (PIP) Complex in Human Dilated Cardiomyopathy

Abstract

Myocardial remodeling is a major contributor in the development of heart failure (HF) after myocardial infarction (MI). Integrin-linked kinase (ILK), LIM-only adaptor PINCH-1, and α-parvin are essential components of focal adhesions (FAs), which are highly expressed in the heart. ILK binds tightly to PINCH-1 and α-parvin, which regulates FA assembly and promotes cell survival via the activation of the kinase Akt. Mice lacking ILK, PINCH or α-parvin have been shown to develop severe defects in the heart, suggesting that these proteins play a critical role in heart function. Utilizing failing human heart tissues (dilated cardiomyopathy, DCM), we found a 2.27-fold (p<0.001) enhanced expression of PINCH, 4 fold for α-parvin, and 10.5 fold (p<0.001) for ILK as compared to non-failing (NF) counterparts. No significant enhancements were found for the PINCH isoform PINCH-2 and parvin isoform β-parvin. Using a co-immunoprecipitation method, we also found that the PINCH-1-ILK-α-parvin (PIP) complex and Akt activation were significantly up-regulated. These observations were further corroborated with the mouse myocardial infarction (MI) and transaortic constriction (TAC) model. Thymosin beta4 (Tβ4), an effective cell penetrating peptide for treating MI, was found to further enhance the level of PIP components and Akt activation, while substantially suppressing NF-κB activation and collagen expression—the hallmarks of cardiac fibrosis. In the presence of an Akt inhibitor, wortmannin, we show that Tβ4 had a decreased effect in protecting the heart from MI. These data suggest that the PIP complex and activation of Akt play critical roles in HF development. Tβ4 treatment likely improves cardiac function by enhancing PIP mediated Akt activation and suppressing NF-κB activation and collagen-mediated fibrosis. These data provide significant insight into the role of the PIP-Akt pathway and its regulation by Tβ4 treatment in post-MI.

Effects of thymosin β4 and its N-terminal fragment Ac-SDKP on TGF-β-treated human lung fibroblasts and in the mouse model of bleomycin-induced lung fibrosis

“…Nevertheless, it is interesting to note that in both experimental models an early increase in Tb4 expression resulted as a consequence of organ injury, thus confirming Tb4 role in tentative endogenous wound healing that yet is overwhelmed by noxious stimuli. On the other hand, exogenous Tb4 significantly reduced interstitial cardiac fibrosis suppressing collagen expression and thus promoted cardiac function and repair in a myocardial infarction mouse model [20,21]. Remarkably, the Tb4 administration route (either systemic through i.p.…”

Loss of Cardiomyocyte Integrin-Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice

“…7,15 ILK functions include both mechanosensitive properties 2 and action as a kinase. 8 Cardioprotective protein kinase B is an important target of ILK phosphorylation: the cardiomyopathy resulting from loss of ILK phosphorylation in PINCH-inactivated zebrafish is reversed by overexpression of constitutively activated protein kinase B.…”

Thymosin Beta‐4 Is Elevated in Women With Heart Failure With Preserved Ejection Fraction

“…TB4 has been shown to inhibit the NF‐κB pathway in a mouse model of myocardial infarction53 and in tumor necrosis factor α–stimulated corneal epithelial cells 54. We also note that inhibition of NF‐κB resulted in suppression of TB4 expression in a prior study of melanoma cells 55…”