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Limana F.,Centro Cardiologico Monzino Istituto Of Ricovero ra rattere Scientifico Irccs | Esposito G.,Laboratorio Of Patologia Vascolare | D'Arcangelo D.,Laboratorio Of Patologia Vascolare | Di Carlo A.,Laboratorio Of Patologia Vascolare | And 7 more authors.

Aims: HMGB1 injection into the mouse heart, acutely after myocardial infarction (MI), improves left ventricular (LV) function and prevents remodeling. Here, we examined the effect of HMGB1 in chronically failing hearts. Methods and Results: Adult C57 BL16 female mice underwent coronary artery ligation; three weeks later 200 ng HMGB1 or denatured HMGB1 (control) were injected in the peri-infarcted region of mouse failing hearts. Four weeks after treatment, both echocardiography and hemodynamics demonstrated a significant improvement in LV function in HMGB1-treated mice. Further, HMGB1-treated mice exhibited a ~23% reduction in LV volume, a ~48% increase in infarcted wall thickness and a ~14% reduction in collagen deposition. HMGB1 induced cardiac regeneration and, within the infarcted region, it was found a ~2-fold increase in c-kit+ cell number, a ~13-fold increase in newly formed myocytes and a ~2-fold increase in arteriole length density. HMGB1 also enhanced MMP2 and MMP9 activity and decreased TIMP-3 levels. Importantly, miR-206 expression 3 days after HMGB1 treatment was 4-5-fold higher than in control hearts and 20-25 fold higher that in sham operated hearts. HMGB1 ability to increase miR-206 was confirmed in vitro, in cardiac fibroblasts. TIMP3 was identified as a potential miR-206 target by TargetScan prediction analysis; further, in cultured cardiac fibroblasts, miR-206 gain- and loss-of-function studies and luciferase reporter assays showed that TIMP3 is a direct target of miR-206. Conclusions: HMGB1 injected into chronically failing hearts enhanced LV function and attenuated LV remodelling; these effects were associated with cardiac regeneration, increased collagenolytic activity, miR-206 overexpression and miR-206 -mediated inhibition of TIMP-3. © 2011 Limana et al. Source

Simiele F.,University of Chieti Pescara | Recchiuti A.,University of Chieti Pescara | Mattoscio D.,University of Chieti Pescara | De Luca A.,University of Chieti Pescara | And 10 more authors.
FASEB Journal

Lipoxin (LX) A 4, a main endogenous stopsignal of inflammation, activates the G-protein-coupled receptor FPR2/ALX, which triggers potent anti-inflammatory signaling in vivo. Thus, the regulation of FPR2/ALX expression may have pathophysiological and therapeutic relevance. Here, we mapped a nucleotide sequence with strong FPR2/ALX promoter activity. Chromatin immunoprecipitation revealed specificity protein 1 (Sp1) binding to the core promoter. Site-directed mutagenesis of the Sp1 cis-acting element and Sp1 overexpression established that this transcription factor is key for maximal promoter activity, which is instead suppressed by DNA methylation. LXA 4 enhanced FPR2/ALX promoter activity (+74%) and mRNA expression (+87.5%) in MDAMB231 cells. A single nucleotide mutation (A/G) was detected in the core promoter of one subject with history of cardiovascular disease and of his two daughters. This mutation reduced by ∼35-90% the promoter activity in vitro. Moreover, neutrophils from individuals carrying the A/G variant displayed ∼10- and 3-fold reduction in FPR2/ALX mRNA and protein, respectively, compared with cells from their relatives or healthy volunteers expressing the wild-type allele. These results uncover FPR2/ ALX transcriptional regulation and provide the first evidence of mutations that affect FPR2/ALX transcription, thus opening new opportunities for the understanding of the LXA 4-FPR2/ALX axis in human disease. © FASEB. Source

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