Abstract 436: Deregulation of Xbp1 Expression Contributes to Impaired Cardiac Vegf Expression and Angiogenesis During Progression From Cardiac Hypertrophy to Failure in vivo
Background: Increased angiogenic factor expression and enhanced coronary angiogenesis is an adaptive response to increased workload during cardiac hypertrophy. Disruption of coordinated tissue growth and cardiac angiogenesis in the heart contributes to the progression from adaptive cardiac hypertrophy to heart failure, but its molecular mechanisms remained unknown. The aim of the present study was to establish a role for the unfolded protein response (UPR) in the deregulation of proangiogenic factor VEGF expression and cardiac angiogenesis and potential regulatory mechanisms in hypertrophic and failing heart.
Methods and results: Compared to normal control, VEGF-A expression was increased in failing human heart tissue and blood samples, which correlated with the levels of XBP-1, a key unfolded protein response (UPR) inducible transcription factor. Consistently, Western blots showed that cardiac expression of XBP-1 and VEGF-A were induced in the early adaptive phase, but decreased in the maladaptive phase in rat hypertrophic and failing heart. Similarly, Experiments in cultured cardiomyocytes H9c2 (2-1) cells showed that UPR-induced VEGF-A up regulation was determined by XBP-1 expression level. Furthermore, XBP1 was measured as a target of miR-30* by targeting 3′ UTR. Finally, we found that miR-30* was significantly reduced in the early phase of cardiac hypertrophic animal model and in human failing hearts but was increased in the maladaptive diseased heart.
Conclusion: These results suggest that miR-30*/XBP1 regulates VEGF-mediated cardiac angiogenesis, which regulates the transition of adaptive hypertrophy into heart failure. This revealed miR-30*/XBP1/VEGF pathwagy might provide potential diagnosis value and novel targets for prevention and treatment of heart failure.
Author Disclosures: Q. Duan: None. C. Chen: None. P. Wang: None. L. Ni: None. L. Yang: None. D. Wang: None.
- © 2015 by American Heart Association, Inc.