Phillips, C. M.; Zeitz, M. J.; Sapp, E. H.; Abouelenein, K. M.; Smyth, J. W.

Cardiovascular disease remains the leading cause of death globally, underscoring the need for physiologically relevant models to investigate mechanisms of heart failure and arrhythmia. Chronic activation of hypoxic signaling pathways, particularly via the hypoxia-inducible factor (HIF) axis, is a key contributor to cardiac remodeling under stress. A major regulator of HIF signaling is the von Hippel-Lindau tumor suppressor (VHL) which, under normoxic conditions, targets HIF for proteasomal degradation. Loss of VHL results in HIF accumulation and persistent hypoxic signaling, but constitutive cardiomyocyte-specific Vhl knockout models are confounded by developmental effects and early mortality. Here, we develop and characterize an inducible, cardiomyocyte-specific Vhl knockout mouse model as a non-invasive and temporally controlled system to study chronic hypoxic stress and its contribution to cardiac remodeling and disease. VhlLoxP/LoxP;MHC-MerCreMer+/- mice were administered tamoxifen to induce Vhl deletion in adult cardiomyocytes. Within 5-7 days post-induction, mice displayed reduced ejection fraction, increased cardiac diameter, and elevated expression of cardiac stress markers. Transcriptomic and protein analyses revealed downregulation of key genes involved in cardiac structure and electrophysiology, including Gja1 (Cx43), Cdh2 (N-cadherin), Cacna1c (CaV1.2), and Kcnq1. Importantly, these changes preceded overt cardiac remodeling, as confirmed in an abbreviated tamoxifen protocol. This inducible Vhl knockout model recapitulates hallmark features of dilated cardiomyopathy and highlights a subset of cardiac structural and ion channel genes as sensitive early responders to chronic hypoxic stress. This platform enables mechanistic dissection of disease onset and progression in ischemic heart disease and serves as a well-controlled and reproducible model for evaluating novel therapeutic strategies.