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RSK3 (p90 ribosomal S6 kinase 3) in the cardiomyocyte is required for the induction of pathological cardiac remodeling through its action at perinuclear signalosomes organized by the scaffold protein muscle A-kinase anchoring protein β (mAKAPβ). At mAKAPβ, RSK3 phosphorylates the transcription factor serum response factor in response to adrenergic stimulation, promoting concentric cardiac hypertrophy and interstitial myocardial fibrosis. We have developed a novel preclinical Ossabaw swine model of cardiometabolic heart failure featuring metabolic syndrome (obesity, insulin resistance, dyslipidemia) and cardiovascular dysfunction including concentric hypertrophy, diastolic dysfunction, preserved ejection fraction, and pulmonary edema. The purpose of this study was to examine a novel gene therapy that displaces RSK3 on mAKAPβ by adeno-associated virus (AAV)-based expression of a RSK3|mAKAPβ anchoring disruptor peptide (RBD) in cardiomyocytes (AAV9sc.RBD). We hypothesized that disruption of RSK3|mAKAPβ by AAV9sc.RBD would improve cardiac function and decrease pulmonary congestion. Female Ossabaw pigs were assigned to HF control (HF; n=4-5) and HF AAV9sc.RBD-treated (HF+RBD; n=4-7) groups. Animals were fed a Western diet (3 mo. old) and aortic banded (6 mo. old) prior to terminal experiments (12 mo. old). Peripheral intravenous saline containing 3 x 1014 viral genomes (vg) of AAV9sc.RBD biologic was infused immediately after aortic banding. Pressure-volume hemodynamics were used to measure cardiac function, and group comparisons were made using student’s t-test or Mann-Whitney test with significance reported at the P≤0.05 level. 0.9-2.5 x104 vg|μg genomic DNA was delivered in the heart, equivalent to ~0.4-1.2 virion per adult swine cardiomyocyte. Wet lung weight was decreased in HF+RBD animals compared to HF (283±19 vs. 423±64 g) and associated with improved diastolic function evident by a decrease in the withend diastolic pressure-volume relationship (EDPVR: 0.039±0.004 vs. 0.022±0.003 mmHg|mL). Stroke volume was increased in the HF+RBD group (40±2 vs. 50±2 mL) and associated improved hemodynamic coupling between the left ventricle and peripheral vasculature demonstrated by decreased arterial elastance (Ea; 2.3±0.2 vs. 1.7±0.2 mmHg|mL) and the ventricular-arterial coupling ratio (Ea|ESPVR; 0.14±0.03 vs. 0.06±0.0.01, P=0.06). These data suggest AAV9sc.RBD-mediated disruption of RSK3|mAKAPβ signalosomes in the cardiomyocyte improves cardiac function and ventricular-vascular interaction, highlighting the potential of gene therapy for treating cardiometabolic heart failure Department of Defense (DOD) W81XWH-18-1-0179 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.