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Friday October 5, 2018 -- GJA1-20k: The Great Communicator

SMBB Auditorium 2650, 11:45 am

Speaker: Robin Shaw, Professor of Medicine/ Wasserman Endowed Chair of Cardiology , Smidt Heart Institute, Cedars-Sinai Medical Center and UCLA

Presentation Abstract:

Connexin 43 (Cx43), a product of GJA1 gene, is a gap junction protein facilitating intercellular communication between cardiomyocytes. Cx43 also protects the heart from ischemic injury, by mechanisms not well understood. GJA1 mRNA can undergo alternative translation, generating smaller isoforms in the heart with GJA1-20k being the most abundant. GJA1-20k is essential for full length Cx43 trafficking, as well as localizes to mitochondria, facilitating mitochondrial trafficking as well. We have more recently identified that ischemic and ischemia/reperfusion (I/R) injury upregulates endogenous GJA1-20k protein in the heart, targeting the outer mitochondrial membrane. Exploring the consequence of increased GJA1-20k, we find that AAV9-mediated gene transfer of GJA1-20k in mice hearts reduces mitochondrial membrane potential, respiration and ROS production while increasing mitochondrial biogenesis. By doing so, GJA1-20k promotes a protective mitochondrial phenotype as seen with ischemic preconditioning (IPC), which also results in increased GJA1-20k levels. Pre-treatment of the heart with exogenous AAV9-GJA1-20k reduces myocardial infarct size in an in-vivo model of cardiac ischemic injury and preserves cardiac muscle and intraventricular pressure in an ex-vivo model of I/R, to a better extent than with IPC. We conclude that endogenous GJA1-20k is a potent stress response protein that induces mitochondrial biogenesis and metabolic hibernation, thus preconditioning the heart and providing cardioprotection from ischemic insults. Exogenous introduction of GJA1-20k is a putative therapeutic for patients undergoing anticipated ischemic injury.

Faculty Host: Frank Sachse, Rob MacLeod