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Abstract Myocardial infarction is still a life-threatening disease, even though its prognosis has been improved through the development of percutaneous coronary intervention and pharmacotherapy. In addition, heart failure due to remodeling after myocardial infarction requires lifelong management. The aim of this study was to develop a novel treatment suppressing the myocardial damage done by myocardial infarction. We focused on inhibition of soluble epoxide hydrolase to prolong the activation of epoxyeicosatrienoic acids, which have vasodilatory and anti-inflammatory properties. We successfully made a new vaccine to inactivate soluble epoxide hydrolase, and we have evaluated the effect of the vaccine in a rat myocardial infarction model. In the vaccinated group, the ischemic area was significantly reduced, and cardiac function was significantly preserved. Vaccine treatment clearly increased microvessels in the border area and suppressed fibrosis secondary to myocardial infarction. This soluble epoxide hydrolase vaccine is a novel treatment for improving cardiac function following myocardial infarction.

Abstract Background Glucagon-like peptide-1 (GLP-1) reduces cardiovascular events in diabetic patients; however, its counter-protective effects have also been suggested in patients with heart failure and the clear explanation for its mechanisms have not yet been offered. Methods The effects of GLP-1 analog on cardiac function and energy metabolism, especially glycemic and lipid metabolisms were elucidated using non-diabetic J2N-k hamsters which showed spontaneous dilated cardiomyopathy. J2N-k hamsters were treated with PBS (HF group), low-dose (HF-L group) or high-dose liraglutide (HF-H group). Results In failing heart, GLP-1 analog exerted further deteriorated cardiac function (e.g. positive and negative dP/dt; p = 0.01 and p = 0.002, respectively) with overt fibrosis and cardiac enlargement (heart/body weight, 5.7 ± 0.2 in HF group versus 7.6 ± 0.2 in HF-H group; p = 0.02). The protein expression of cardiac muscles indicated the energy starvation status. Indirect calorimetry showed that failing hearts consumed higher energy and carbohydrate than normal hearts; moreover, this tendency was augmented by GLP-1 analog administration. Upon 10% glucose solution loading with GLP-1 analog administration (HF-H-G group) as complementary experiments, the cardiac function and fibrosis significantly ameliorated, whereas carbohydrate utilization augmented further and lipid utilization reduced more. The prognosis of HF-H-G group also significantly improved (p = 0.025). Conclusions Glucagon-like peptide-1 analog caused the relative but desperate shortage of glycemic energy source for the failing cardiac muscles and it may restrict ATP synthesis, resulting in cardiac function deterioration. Therefore, appropriate energy supply and amount of carbohydrate intake should be carefully considered when administrating incretin-related drugs to patients with heart failure.

Background and aims: Pentraxin-3 (PTX3) reportedly has protective roles in atherosclerosis and myocardial infarction, and is a useful biomarker of vascular inflammation. However, the detailed functions of PTX3 in inflammation are yet to be elucidated. This study aimed to investigate the function of PTX3 in macrophages. Methods: PMA-treated THP-1 cell line (THP-1 macrophage) and monocyte-derived human primary macrophages were treated with recombinant PTX3. Cytokine and chemokine levels in the THP-1 culture medium were measured as well as monocyte chemoattractant protein (MCP-1) concentrations in the Raw 264.7 cell culture medium. PTX3-silenced apoptotic macrophages (THP-1 cell line) were generated to investigate the roles of PTX3 in phagocytosis. Results: In the presence of PTX3, macrophage interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) and MCP-1 levels were reduced significantly (−39%, P=0.007; −21%, P=0.008; and −67%, P=0.0003, respectively), whilst activated transforming growth factor-β (TGF−β) was detected in the THP-1 macrophages (P=0.0004). Additionally, PTX3 induced Akt phosphorylation and reduced nuclear factor-kappa B (NF-κB) activation by 35% (P=0.002), which was induced by TNF-α in THP-1 macrophages. Furthermore, silencing of PTX3 in apoptotic cells resulted in increased macrophage binding, elevated expression rate of HLA-DR (+30%, P=0.015) and CD86 (+204%, P=0.004) positive cells, and induction of IL-1β (+36%, P=0.024) production. Conversely, adding recombinant PTX3 to macrophages reduced CD86 and HLA-DR expression in a dose-dependent manner. Conclusions: We identified PTX3 as a novel regulator of macrophage activity, and this function suggests that PTX3 acts to resolve inflammation.

BackgroundAn excessive inflammatory response after myocardial infarction (MI) increases myocardial injury. The toll‐like receptor (TLR)‐4 is activated by the recognition of endogenous ligands and is proinflammatory when there is myocardial tissue injury. The apoptosis inhibitor of the macrophage (AIM) is known to provoke an efflux of saturated free fatty acids (FFA) due to lipolysis, which causes inflammation via the TLR‐4 pathway. Therefore, this study investigated the hypothesis that AIM causes a proinflammatory response after MI. Methods and ResultsThe left anterior descending coronary artery was ligated to induce MI in both AIM‐knockout (AIM−/−) and wild‐type (WT) mice. After 3 days, the inflammatory response from activation of the TLR‐4/NFκB pathway was assessed, and infarct size was measured by staining with triphenyltetrazolium chloride. In addition, left ventricular remodeling was examined after 28 days. Although the area at risk was similar between AIM−/− and WT mice, the infarct size was significantly smaller in AIM−/− mice (P=0.02). The heart weight–to–body weight ratio and myocardial fibrosis were also decreased in the AIM−/− mice, and the 28‐day survival rate was improved (P