Abstract
Transcriptomic signature of XPO1 was highly expressed and inversely related to left ventricular function in ischemic cardiomyopathy patients. We hypothesized that treatment with AAV9-shXPO1 attenuates left ventricular dysfunction and remodeling in a myocardial infarction rat model. We induced myocardial infarction by coronary ligation in Sprague-Dawley rats (n = 10), which received AAV9-shXPO1 (n = 5) or placebo AAV9-scramble (n = 5) treatment. Serial echocardiographic assessment was performed throughout the study. After myocardial infarction, AAV9-shXPO1-treated rats showed partial recovery of left ventricular fractional shortening (16.8 ± 2.8 vs 24.6 ± 4.1%, P < 0.05) and a maintained left ventricular dimension (6.17 ± 0.95 vs 4.70 ± 0.93 mm, P < 0.05), which was not observed in non-treated rats. Furthermore, lower levels of EXP-1 (P < 0.05) and lower collagen fibers and fibrosis in cardiac tissue were observed. However, no differences were found in the IL-6 or TNFR1 plasma levels of the myocardium of AAV9-shXPO1 rats. AAV9-shXPO1 administration attenuates cardiac dysfunction and remodeling in rats after myocardial infarction, producing the gene silencing of XPO1.
Highlights
Introduction conforms to theGuide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No 85-23, revised 1996), and the National (RD 53/2013) and European Directive (2010/63/EC)
To determine the efficacy of XPO1 silencing and specificity of the AAV9-shXPO1 vector, we measured EXP-1 levels in different explanted tissues of rats by Western blot
Previous studies in patients with ischemic cardiomyopathy showed elevated expression levels of both EXP-1 mRNA and protein, and interestingly, these levels were inversely related with ejection fraction and positively correlated with LVESD and LV end-diastolic diameters (LVEDD) [8, 9], i.e., higher EXP-1 expression is linked with left ventricular (LV) function impairment
Summary
Introduction conforms to theGuide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No 85-23, revised 1996), and the National (RD 53/2013) and European Directive (2010/63/EC). Adverse ventricular remodeling associated with a higher probability of heart failure and mortality occurs [2, 3], and numerous cellular and molecular pathways are affected [4,5,6,7], such as the existence of various alterations in the molecular machinery of nuclearcytoplasmic transport [8, 9], which precisely regulates the bidirectional selective protein flow between the nucleus and the cytoplasm. Previous studies have shown that several molecules that participate in nuclear-cytoplasmic transport (Exportin-1 [EXP-1], IMP-β3, Nup160) are intimately related to a reduced left ventricular (LV) function in human ischemic cardiomyopathy. The transcriptomic signature of these alterations has been found and has been identified that changes in gene expression, of XPO1 that encodes EXP-1, were highly related to LV dysfunction in patients with ischemic cardiomyopathy [10]
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