SRF and Yap1, partners in cardiac repair
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, 5 min after coronary artery occlusion, reduced infarct size and substantially improved ejection fraction. Alone, however, neither molecule was effective.
Gene delivery to the heart and cardiac myocytes also imposes a challenge, as the commonly utilized recombinant adenoviruses or adeno-associated viruses have their limitations. The former is known for its immunogenicity, while the latter is its longevity. When forcing the myocytes to enter the cell cycle, one of the issues that must be addressed is how to terminate the stimulus in order to allow the proliferating myocytes to differentiate. The authors astutely addressed this dilemma by delivering the short-lived synthetically modified mRNA (mmRNA) of the genes, combined with liposomes, intramyocardially. This approach was first reported by Zangi et al., who showed that intramyocardial injection of mmRNA for vascular endothelial growth factor A (VEGF-A) improved cardiac function in mice with myocardial infarction[5]. Notably, injecting the mmRNA proved superior to injecting the DNA of the gene. Since then, this technology has gained traction, as one of its most recognized uses has been the development of the COVID19 vaccines[6]. To sum up, the combination of STEMIN, YAP5SA, and intramyocardial mmRNA delivery proved to be an effective approach for inducing myocyte proliferation and myocardial repair of the ischemic heart.
DECLARATIONS
Authors’ contributionsThe author contributed solely to the article.
Availability of data and materialsNot applicable.
Financial support and sponsorshipDr. Abdellatif is supported by National Institute of Health grants R01 HL157739.
Conflicts of interestThe author declared that there are no conflicts of interest.
Ethical approval and consent to participateNot applicable.
Consent for publicationNot applicable.
Copyright© The Author(s) 2022.
REFERENCES
1. Payan SM, Hubert F, Rochais F. Cardiomyocyte proliferation, a target for cardiac regeneration. Biochim Biophys Acta Mol Cell Res 2020;1867:118461.
2. Mohamed TMA, Ang YS, Radzinsky E, et al. Regulation of cell cycle to stimulate adult cardiomyocyte proliferation and cardiac regeneration. Cell 2018;173:104-116.e12.
3. Von Gise A, Lin Z, Schlegelmilch K, et al. YAP1, the nuclear target of Hippo signaling, stimulates heart growth through cardiomyocyte proliferation but not hypertrophy. Proc Natl Acad Sci USA 2012;109:2394-9.
4. Xiao S. STEMIN and YAP5SA synthetic modified mRNAs regenerate and repair infarcted mouse hearts. J Cardiovasc Aging 2022;2:31.
5. Zangi L, Lui KO, von Gise A, et al. Modified mRNA directs the fate of heart progenitor cells and induces vascular regeneration after myocardial infarction. Nat Biotechnol 2013;31:898-907.
How to Cite
Abdellatif, M. SRF and Yap1, partners in cardiac repair. J. Cardiovasc. Aging. 2022, 2, 36. http://dx.doi.org/10.20517/jca.2022.23
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