SRF and Yap1, partners in cardiac repair.

Abstract

Therapeutic strategies for the repair of myocardial ischemic damage are an ongoing challenge for both scientists and clinicians. The obstacle is the limited capacity of the terminally differentiated myocytes to proliferate, mainly due to postnatal downregulation of cell cycle proteins and physical hindrance from the perpetually contracting sarcomeres that occupy most of the cells’ volume. Thus far, some of the strategies employed to undertake this challenge include stem cell implantation or injection, inducing myocyte proliferation, or tissue grafting. However, to date, cardiac ischemic damage remains irreparable. Approaches to induce the myocyte to proliferate include suppressing the cyclin-dependent kinase inhibitors (CDKi) by overexpressing a dominant negative FOXO1 or deletion of Meis1, both of which are known to increase CDKi’s [1] . Alternatively, overexpression of cyclins-CDKs (CDK1, CDK4, cyclin B1, and cyclin D1) partners efficiently enhanced myocyte proliferation, as previously reported by Mohamed et al. [2] . These genes were delivered locally via recombinant adenovirus, which, unfortunately, is unsuitable for gene therapy due to its immunogenicity. Another mechanism involves Yap and TAZ, which activate the transcription of cell cycle proteins, where overexpression of a constitutively active YAP enhances adult myocyte proliferation [3] . Uniquely, Xiao et al., in this issue, combined an SRF153(A3) mutant, STEMIN, which lacks the ability to bind the CArG box, with the cell cycle regulator Yap1 [4] . With this combination, STEMIN induces sarcomere disassembly and dedifferentiation of cardiac myocytes, while YAP increases the expression of the necessary cell cycle proteins, which proved to have a synergestic proliferative effect on the cardiac myocytes. Impressively, intramyocardial injections of the mRNA of both molecules,