Decreased arterial elastance following a novel RSK3/mAKAP gene therapy is associated with improved bradykinin-dependent pial artery dilation in aortic-banded, Western diet-fed female Ossabaw swine

Cardiogenic dementia is associated with increased risk of mortality in heart failure. Cognitive decline is more prevalent in females, of which cardiac function is a strong predictor. We have demonstrated cerebrovascular insufficiency in female Ossabaw swine with cardiometabolic heart failure (CM-HF). The purpose of this study was to examine the effect of a novel gene therapy that displaces p90 ribosomal S6 kinase 3 (RSK3) from perinuclear muscle A-kinase anchoring protein β (mAKAPβ) signalosomes using a systemically delivered adeno-associated virus (AAV) to express a RSK3/mAKAPβ anchoring disruptor peptide (RBD) controlled by a cardiomyocyte-specific promoter (AAV9.RBD). We hypothesized that disruption of RSK3/mAKAPβ by AAV9.RBD would improve cardiac and cerebrovascular function in parallel, diminishing cardiogenic pathology. Female Ossabaw pigs were assigned to HF control (HF; n=4) and HF AAV9.RBD-treated (HF+RBD; n=5) groups. Animals were fed a Western diet (3 mo. old) and aortic banded (6 mo. old) prior to euthanasia (12 mo. old). Pressure-volume hemodynamics were used to measure arterial elastance (Ea), the ratio of end systolic pressure:stroke volume (SV). Pressure myography was used to assess in vitro cerebral vascular function (2a pial arterioles; inner diameter 267 ± 19 μm HF & 248 ± 9 μm HF+RBD). Group comparisons were made using student’s t-test and repeated measures ANOVA with significance reported at the P≤0.05 level. Ea was decreased in HF+RBD animals compared to HF (mmHg/mL; 2.3 ± 0.2 HF & 1.7 ± 0.2 HF+RBD) and driven by increased SV (mL; 40 ± 2 HF & 50 ± 2 HF+RBD). Decreased arterial load was associated with increased endothelial-dependent dilation to bradykinin (BK) in the HF+RBD group compared to HF (Group x Dose interaction) in isolated pial arteries. BK-induced dilation was decreased in the presence of L-NAME (nitric oxide synthase inhibitor) in HF, but not HF+RBD animals (Group x Dose interaction). In contrast, BK-induced dilation was decreased in the presence of indomethacin (prostaglandin synthesis inhibitor) only in the HF+RBD group (Group x Dose interaction). In conclusion, decreased cardiac arterial load (Ea) was coupled with improved endothelial-dependent cerebral vascular function that was mechanistically characterized by altered nitric oxide/prostaglandin balance in female Ossabaw swine with CM-HF. These findings suggest AAV9.RBD-mediated disruption of RSK3/mAKAPβ signalosomes in cardiomyocytes has a positive cardiogenic effect on cerebrovascular function. 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.