VGLL4 and IRF2BP2 regulation of cardiomyocyte survival and hypertrophy

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After myocardial infarction (MI), massive cardiomyocyte (CM) loss occurs due to apoptosis and necrosis. The surviving myocardium undergoes hypertrophic remodeling, which is beneficial in short term but detrimental in the long run. Dissecting the molecular mechanisms controlling cardiomyocyte hypertrophy and survival is critical to permit development of new heart failure therapeutic drugs. One signature of cardiac hypertrophy remodeling is the up regulation of a characteristic hypertrophic gene program, but it is not clear how these genes are activated, and which of these gene expression changes are beneficial or detrimental in heart injury or stress. The Hippo-YAP pathway is a key growth regulatory pathway conserved from flies to mammals. YAP, the terminal effector of this pathway, functions by binding to TEAD family transcription fac- tors. Data from our lab and other labs showed that the Hippo-Yap pathway is essential for car- diac development and cardiac repair. Vestigial like 4 (VGLL4), TEAD co-factor that suppresses YAP activity in mitotic tissues, is expressed preferentially in cardiomyocytes, where we have found that it is present both in the nucleus and in mitochondria. Our recent studies, now in press at Developmental Cell, show that VGLL4 antagonizes cardiac YAP-TEAD activity and is regu- lates postnatal cardiac maturation. Our preliminary data show that VGLL4 is essential for main- taining cardiac function. Another transcriptional regulator, IRF2BP2, is a major interaction partner of VGLL4 in cardiomyocytes. Our preliminary data show that IRF2BP2 is sufficient to suppress cardiomyocyte hypertrophic growth by attenuating NFAT signaling. Thus, VGLL4- IRF2BP2 form a previously unrecognized nodal point in cardiac hypertrophic signaling that likely also intersects with Hippo/YAP signaling. This proposal builds on these findings, aiming to dis- cover new molecular mechanisms regulating cardiomyocyte hypertrophy and survival. Integral to this study will be the development of therapeutically relevant adeno-associated virus (AAV) reagents for proof-of-concept pre-clinical gene therapy studies in mice. Specific Aims: Aim 1. To explore the roles of VGLL4 in the regulation of adult CM survival. We will study the mechanism of VGLL4 regulation CM survival, and engineer VGLL4 to tailor its activity for treating heart fail- ure. Aim 2. Study the mechanisms by which IRF2BP2 regulates cardiomyocyte hypertrophy. We will do both cardiac specific gain- and loss-of-function studies with IRF2BP2 in the normal heart, focusing on characterizing the cardiac phenotype. We will also test whether IRF2BP2 ac- tivation in the MI model decreases cardiac hypertrophic remodeling and CM death. Aim 3. Identify components of the hypertrophic gene program regulated by both IRF2BP2 and VGLL4. We will test whether IRF2BP2 activates cardiac fetal gene expression by alleviating VGLL4 sup- pression of TEAD1. These studies will inform efforts to improve heart function and suppress detrimental cardiac remodeling. -1-