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XPO1 gene therapy restores cardiac function in rats with chronic induced myocardial infarction
bioRxiv
Publisher: Cold Spring Harbor Laboratory
Abstract
Background In previous studies, we showed that several nuclear-cytoplasmic transport molecules were closely related to ventricular dysfunction in human heart failure. Particularly, the transcriptomic signature of XPO1 was highly expressed and inversely related to left ventricular function in heart failure patients of ischemic etiology. Therefore, we hypothesized that in a rat model of myocardial infarction treated with AAV9-shXPO1, an improvement in the ventricular function after a follow-up period may be observed.Methods We induced myocardial infarction by coronary ligation in Sprague-Dawley rats (n=10), five of them received AAV9-shXPO1 treatment after four months and the other five infarcted rats did not receive any treatment. For non-failing controls, healthy Sham rats (n=5) received the placebo AAV9-scramble. Serial echocardiographic assessment was performed before, as well as, two and five months after intravenous injection.Results AAV9-shXPO1-treated rats showed improved fractional shortening (16.8 ± 2.8 vs 24.6 ± 4.1%, P<0.05) and LV systolic (5.10 ± 0.79 vs 3.52 ± 0.88mm, P<0.05) and diastolic (6.17 ± 0.95 vs 4.70 ± 0.93mm, P<0.05) diameters when comparing measurements obtained before and five months after AAV9 injection. We did not observe this improvement in untreated infarcted rats. Furthermore, EXP-1 levels in rats heart, brain, skeletal muscle, and liver were determined by western-blot and compared to controls in AAV9-shXPO1-treated rats. Lower levels of EXP-1 in cardiac tissue were observed (P<0.05).Discussion At five months follow-up, ischemic AAV9-shXPO1-treated rats showed partial recovery of LV myocardial function. No secondary symptoms attributable to AAV9-shXPO1 were observed in skeletal muscle, liver and brain.