Abstract Wed061: An Inducible Genetic Model of Chronic Cardiomyocyte-specific Hypoxic Signaling Elicits Rapid Cardiac Remodeling

Background: Cardiovascular disease is the leading cause of death in the United States, with a continuing need to understand molecular mechanisms of heart failure and arrhythmia. A potential method for reproducibly modeling heart disease in vivo involves genetic manipulation of the hypoxia inducible factor (HIF) pathway. During normoxia, Von Hippel-Lindau tumor suppressor (VHL, gene name Vhl ) targets HIFα for degradation. VHL loss mimics hypoxic stress through preventing HIFα degradation, leading to transcriptional activation/repression of responsive genes. While constitutive cardiomyocyte-specific Vhl knockout ( Vhl -/- ) mice display cardiac abnormalities, lack of temporal control introduces developmental effects. An inducible model would be favorable for more controlled insult to model chronic cardiac hypoxic stress in vivo in adult animals. We aimed to establish an inducible cardiomyocyte-specific Vhl -/- mouse line to model chronic cardiac hypoxic stress in vivo . Methods: Vhl-LoxP/LoxP ;αMHC-MerCreMer +/- mice were induced with tamoxifen administration over 3-5 day timecourses. Cardiac function and structure were assessed via echocardiography (n = 6-8). Cardiac transcript and protein expression were investigated through RNAseq (n = 3), RT-qPCR (n = 5-8), and western blot (n = 5-8). Results: As early as 5 days post induction, Vhl -/- mice display decreased ejection fraction and increased cardiac diameter. At day 8, Vhl -/- hearts demonstrate increased mRNA levels of cardiac stress markers and reduced mRNA levels of critical cardiac structural and electrophysiological genes including: Cdh2 (N-cadherin), Cacna1c (Ca V 1.2), and Kcnq1 (KQT member 1), together with severely reduced mRNA and protein levels of the gap junction protein connexin43. To determine whether these molecular changes precede cardiac remodeling, we harvested Vhl -/- hearts at day 3 and found altered expression of key cardiac structural and functional genes levels by RNAseq. Conclusions: We find that cardiomyocyte-specific chronic hypoxic signaling precipitates cardiac remodeling analogous to dilated cardiomyopathy. At the molecular level, expression of genes crucial for cardiac structure and electrophysiology are particularly sensitive to chronic hypoxic signaling.