Significance of Thymosin β4 and Implication of PINCH-1-ILK-α-Parvin PIP Complex in Human Dilated CardiomyopathyReport as inadecuate

Significance of Thymosin β4 and Implication of PINCH-1-ILK-α-Parvin PIP Complex in Human Dilated Cardiomyopathy - Download this document for free, or read online. Document in PDF available to download.

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.

Author: Nikolai Sopko, Yilu Qin, Amanda Finan, Alisher Dadabayev, Sravanthi Chigurupati, Jun Qin, Marc S. Penn, Sudhiranjan Gupta



Related documents