Edited by Roger J. Colbran Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication that have the potential to improve cardiac function when used in cell-based therapy. However, the means by which cardiomyocytes respond to EVs remains unclear. Here, we sought to clarify the role of exosomes in improving cardiac function by investigating the effect of cardiomyocyte endocytosis of exosomes from mesenchymal stem cells on acute myocardial infarction (MI). Exposing cardiomyocytes to the culture supernatant of adipose-derived regenerative cells (ADRCs) prevented cardiomyocyte cell damage under hypoxia in vitro. In vivo, the injection of ADRCs into the heart simultaneous with coronary artery ligation decreased overall cardiac infarct area and prevented cardiac rupture after acute MI. Quantitative RT-PCR-based analysis of the expression of 35 known anti-apoptotic and secreted microRNAs (miRNAs) in ADRCs revealed that ADRCs express several of these miRNAs, among which miR-214 was the most abundant. Of note, miR-214 silencing in ADRCs significantly impaired the anti-apoptotic effects of the ADRC treatment on cardiomyocytes in vitro and in vivo. To examine cardiomyocyte endocytosis of exosomes, we cultured the cardiomyocytes with ADRC-derived exosomes labeled with the fluorescent dye PKH67 and found that hypoxic culture conditions increased the levels of the labeled exosomes in cardiomyocytes. Chlorpromazine, an inhibitor of clathrin-mediated endocytosis, significantly suppressed the ADRC-induced decrease of hypoxia-damaged cardiomyocytes and also decreased hypoxia-induced cardiomyocyte capture of both labeled EVs and extracellular miR-214 secreted from ADRCs. Our results indicate that clathrin-mediated endocytosis in cardiomyocytes plays a critical role in their uptake of circulating, exosome-associated miRNAs that inhibit apoptosis.

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Objective Cardiovascular disease is a leading cause of death worldwide. Obesity-related metabolic disorders including dyslipidemia cause impaired collateralization under ischemic conditions, thereby resulting in exacerbated cardiovascular dysfunction. Pemafibrate is a novel selective PPARα modulator, which has been reported to improve atherogenic dyslipidemia, in particular, hypertriglyceridemia and low HDL-cholesterol. Here, we investigated whether pemafibrate modulates the revascularization process in a mouse model of hindlimb ischemia.

Background: The purpose of the study was to evaluate the impact of nutritional status on 1-year mortality in hospitalized patients with acute decompensated heart failure (ADHF). Methods and Results: We enrolled 457 hospitalized ADHF patients. Previously established objective nutritional indexes (controlling nutritional status [CONUT], prognostic nutritional index [PNI], geriatric nutritional risk index [GNRI], and subjective global assessment [SGA]) were evaluated at hospital admission. Malnutrition was defined as CONUT score ≥5, PNI score <38, GNRI score <92, and SGA scores B and C. The frequencies of malnutrition based on CONUT, PNI, GNRI, and SGA were 31.5%, 21.4%, 44.9%, and 27.8%, respectively. All indexes were related to the occurrence of 1-year mortality on univariate Cox regression analysis (P<0.05). We constructed a reference model using age, body mass index, systolic blood pressure, sodium concentration, and renal function on multivariable Cox regression analysis. Adding SGA to the reference model significantly improved both net reclassification improvement (NRI) and integrated discrimination improvement (0.344, P=0.002; 0.012, P=0.049; respectively). Other indexes (CONUT, PNI, and GNRI scores) significantly improved NRI (0.254, P=0.019; 0.273, P=0.013; 0.306, P=0.006; respectively). Conclusions: Nutritional screening assessed at hospital admission was appropriate for the prediction of 1-year mortality in hospitalized patients with ADHF.

Aims Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein-E knockout (apoE-KO) mice. Methods and Results ApoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate ApoE-KO/OMT-Tg mice. ApoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. ApoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apo-E KO mice. ApoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibers in response to Ang II compared with apo-E KO mice. ApoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2 and pro-inflammatory genes in aortic walls compared with apo-E KO mice. Furthermore, systemic administration of omentin also attenuated AAA formation and disruption of medial elastic fibers in response to Ang II in apoE-KO mice. Treatment of human monocyte-derived macrophages with omentin protein attenuated expression of MMP9 and pro-inflammatory mediators, and MMP9 activation after stimulation with lipopolysaccharide (LPS). Treatment of human vascular smooth muscle cells with omentin protein reduced expression and activation of MMP2 after stimulation with tumor necrosis factor α. Omentin treatment increased phosphorylation levels of Akt in human macrophages and vascular smooth muscle cells. The suppressive effects of omentin on MMP9 and MMP2 expression were reversed by inhibition of integrin-αVβ3/PI3-kinase/Akt signaling in macrophages and vascular smooth muscle cells, respectively. Conclusion These data suggest that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA through suppression of MMP9 and MMP2 expression and inflammatory response in the vascular wall.