Targeted inhibition of perinuclear β-adrenergic receptors using ONM-Nb80 preserved left ventricular ejection fraction following ischemia-reperfusion injury in a murine model.
RCT
randomized
Does targeted inhibition of perinuclear β-adrenergic receptors using ONM-Nb80 preserve cardiac function in a murine model of ischemia-reperfusion injury?
Targeted inhibition of perinuclear β-adrenergic receptors via gene therapy preserves left ventricular function and prevents adverse remodeling in a murine model of ischemia-reperfusion injury.
Background: β-adrenergic receptor (βAR) signaling is a central regulator of cardiac stress responses. Recent evidence suggests that spatially restricted βAR pools, including perinuclear βARs resident on the Golgi apparatus, may differentially regulate pathological versus adaptive remodeling. Whether perinuclear βAR signaling contributes to myocardial injury and remodeling following ischemia–reperfusion (I/R) injury remains unknown. Methods: To test the role of perinuclear βARs in ischemic cardiomyopathy, we employed a cardiomyocyte-targeted gene therapy approach in a murine model of myocardial I/R injury. Adult C57BL/6NJ mice were randomized to receive AAV9 expressing a nesprin-1α - βAR Nb80 nanobody fusion protein localized to the outer nuclear membrane (ONM-Nb80), AAV9 ONM-control vector, or no AAV. Four weeks after AAV delivery, mice underwent transient left anterior descending coronary artery occlusion (45 min) followed by reperfusion. Cardiac function was assessed longitudinally 24 hours and 8 weeks post I/R using echocardiography and 4D LV global stain by speckle-tracking echocardiography. Results: In control-treated and AAV-naïve mice, I/R injury resulted in a progressive decline in left ventricular systolic function, ventricular dilation, and impaired contraction. In contrast, mice expressing ONM-Nb80 exhibited significant preservation of left ventricular ejection fraction following I/R injury, accompanied by reduced end-systolic volume compared with control cohorts. Importantly, ONM-Nb80 treatment did not adversely affect baseline cardiac function in sham-operated mice. Conclusions: Targeted inhibition of perinuclear βAR signaling confers protection against ischemia–reperfusion–induced cardiac dysfunction and adverse remodeling. These findings identify perinuclear βARs as key mediators of pathological post-ischemic remodeling and provide initial proof of concept for spatially restricted βAR targeting as a therapeutic strategy to limit myocardial injury and promote functional recovery following ischemia–reperfusion. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Samuelsson et al. (Fri,) conducted a rct in Myocardial ischemia-reperfusion injury. AAV9 expressing ONM-Nb80 vs. AAV9 ONM-control vector or no AAV was evaluated on Cardiac function (left ventricular ejection fraction and end-systolic volume). Targeted inhibition of perinuclear β-adrenergic receptors using ONM-Nb80 preserved left ventricular ejection fraction following ischemia-reperfusion injury in a murine model.