Browsing by Author "Lago Paz, Francisca"

Accumulating evidence has confrmed that the expression of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) is downregulated in heart failure and cardiac allograft rejection. Although many SERCA2arelated genes and proteins involved in the regulation of myocardial Ca2+ fuxes have been explored, its related metabolites remain poorly studied. Our main objective was to identify circulating SERCA2arelated metabolites altered in cardiac allograft rejection and to determine whether these could serve as non-invasive biomarkers. Sixty plasma samples from adult heart transplant were included in a metabolomic analysis. Sphingosine-1 phosphate (S1P), metabolite closely related with SERCA, were increased in patients with cardiac rejection (p<0.0001). S1P discriminated between patients with and without rejection: normal grafts vs. all rejecting grafts (AUC=0.911, p<0.0001), normal grafts vs. Grade 1R (AUC=0.819, p<0.01), Grade 2R (AUC=0.911, p<0.0001), Grade 3R (AUC=0.996, p<0.0001). In addition, we found changes in key enzymes and receptors of S1P pathway analysed on explanted hearts from heart failure patients. This preliminary study reveals that circulating S1P determination could be a novel approach to detect cardiac rejection, showing a robust capability for detection that improves gradually with the severity of rejection. These alterations could be relevant to better understand the involvement of calcium regulation on the pathophysiology of rejection.

Transcriptomic signature ofXPO1was highly expressed and inversely related to left ventricular function in ischemic cardiomy-opathy patients. We hypothesized that treatment with AAV9-shXPO1 attenuates left ventricular dysfunction and remodeling in amyocardial infarction rat model. We induced myocardial infarction by coronary ligation in Sprague-Dawley rats (n= 10), whichreceived AAV9-shXPO1 (n= 5) or placebo AAV9-scramble (n= 5) treatment. Serial echocardiographic assessment was per-formed throughout the study. After myocardial infarction, AAV9-shXPO1-treated rats showed partial recovery of left ventricularfractional 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 lowercollagen fibers and fibrosis in cardiac tissue were observed. However, no differences were found in the IL-6 or TNFR1 plasmalevels of the myocardium of AAV9-shXPO1 rats. AAV9-shXPO1 administration attenuates cardiac dysfunction and remodelingin rats after myocardial infarction, producing the gene silencing ofXPO1.