RhoA and sphingosine -1-phosphate in cardioprotection
This project focuses on the mechanisms by which the low molecular weight G-protein, RhoA, serves a nodal function in protecting cardiomyocytes from stress. Stimuli that activate cardiac RhoA include sphingosine-1-phosphate (S1P) and other ligands for a subset of G-protein coupled receptors (GPCRs) that couple to the G12/13 family of G-proteins. These ligands are generated in response to ischemic stress and inflammation and can stimulate multiple pleiotropic effects of RhoA which protect the heart from damage. Our previous work identified a mechanism for acute protection against ischemia reperfusion injury involving phosphorylation of cofilin2 and altered translocation of Bax to mitochondria. Recent studies demonstrated that mitochondrial fission was regulated through S1P and RhoA dependent phosphorylation of
Drp1. We also showed that the S1P receptor that mediates RhoA activation and cardioprotection is S1P3. Our current work tests the hypothesis that RhoA signaling through transcriptional gene regulation could provide an additional mechanism for protection against cardiac stress. We are specifically examining activation of transcription factors regulated downstream of RhoA (MRTF-A, YAP, NFkB) in WT vs RhoA KO mice to identify genes that are potential mediators of salutary effects of RhoA activation in ischemia/reperfusion, focusing on genes that modulate reactive oxygen accumulation or generate factors that are released and act on cardioprotective pathways. The involvement of YAP signaling in these responses will be tested using cardiac specific YAP knockout mice .The biomedical significance of this work is in elucidating pathways elicited by GPCR agonists or interventions that activate RhoA and YAP in the heart. Further understanding of downstream molecular mechanisms would provide the basis for therapeutic interventions to selectively enhance salutary vs. deleterious effects of RhoA.
Del Re D.P., Miyamoto S. and Brown J.H. Fak as a RhoA-activable signaling scaffold mediating Akt activation and cardiomyocyte protection. J Biol Chem 283:35622-35629, 2008.
Xiang S. Y., Vanhoutte D., Del Re D. P., Purcell N.H., Ling H., Banerjee I., Bossuyt J., Lang R.A., Zheng Y., Matkovich S.J., Miyamoto S., Molkentin J.D., Dorn II G.W. 2nd, and Brown J.H.. RhoA protects the mouse heart against ischemia/reperfusion injury. J. Clin Invest, 121: 3269-3276 2011.
Xiang S.Y., Ouyang K., Miyamoto S., Smrcka A.V., Chen J., Brown J.H., Phospholipase C epsilon, PKD1 and SSH1L transduce RhoA signaling to protect mitochondria from oxidative stress in the heart. Science Signaling, 17;6(306):ra108, 2013.
Yung, B., Brand, C., Xiang, Y., Purcell, N.H., Gray, C.B.B., Rosen, H., Chun, J., Miyamoto, S., Brown J.H., Selective coupling of the S1P3 receptor subtype to S1P-mediated RhoA activation and cardioprotection, J Mol Cell Cardiol, 103:1-10. 2017.
Brand C. S., Tan V. P., Brown J. H., Miyamoto S. RhoA regulates Drp1 mediated mitochondrial fission through ROCK to protect cardiomyocytes. Cell Signal. 2018 Jun 25; 50: 48-57.