Abstract 9474: Trim35-Mediated Ubiquitination and Degradation of Nuclear PKM2 is Sufficient to Promote Heart Failure

• Published in: Circulation (New York, N.Y.) N.Y.), 2022-11, Vol.146 (Suppl_1), p.A9474-A9474
• Main Authors: Lorenzana Carrillo, Maria A, Gopal, Keshav, Byrne, Nikole, Tejay, Saymon, Saleme, Bruno, Das, Subhash, Zhang, Yongneng, Haromy, Alois S, Eaton, Farah, Mendiola Pla, Michelle, Bowles, Dawn E, Dyck, Jason R, Ussher, John R, Michelakis, Evangelos D, Sutendra, Gopinath
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.146.suppl_1.9474

IntroductionPyruvate Kinase M2 (PKM2) is a glycolytic enzyme that can translocate to the nucleus to regulate different transcription factors (TF) in different tissues or pathologic states. Although its function has been studied extensively in cancer, its biologic role in the heart and specifically terminally differentiated adult cardiomyocytes remains unresolved. HypothesisPKM2 may be critical in regulating cardiomyocyte(CM)-specific TF important for cardiac survival. MethodsTransverse aortic constriction (TAC) banding model was used to assess the levels and modifications of PKM2 during heart failure (HF). CM-specific PKM2-deficient and CM-specific Trim35 overexpressing(OE) mice were generated to evaluate the role of PKM2/Trim35 in adult CM. Human Dilated Left Ventricle biopsies were used to translate mechanistic findings into a clinical setting. ResultsHere we show that nuclear PKM2 (S37P-PKM2) in CM interacts with several pro-survival or pro-apoptotic TF, including Gata-4, Gata-6, and p53. CM-specific PKM2-deficient mice developed age-dependent dilated cardiac dysfunction and had decreased levels of Gata-4/6, but increased levels of p53, compared to control Cre+ hearts. Mechanistically, we found that nuclear PKM2 can prevent caspase-1 dependent cleavage Gata-4/Gata-6, while also providing a platform for Mdm2-mediated ubiquitination of p53. In a preclinical HF model, nuclear PKM2, along with Gata-4/6 levels decreased, but p53 levels increased (compared to sham controls). Loss of nuclear PKM2 was ubiquitination-dependent and associated with the induction of the E3 ubiquitin-ligase TRIM35. CM-specific Trim35 OE mice had decreased S37P-PKM2 and GATA-4/6, along with increased p53 levels (compared to littermate controls) and had similar cardiac dysfunction to CM-specific PKM2-deficient mice. In a well-characterized cohort of patients with dilated left ventricles, we found a significant increase in TRIM35 levels that was associated with a decrease in S37P-PKM2, Gata-4/6 levels, but an increase in p53 levels, compared to non-failing ventricles. ConclusionThis study provides insight into a previously unrecognized biologic role for PKM2 in providing a molecular platform for TF essential for preserving cardiac survival.