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Objectives We recently developed a novel peptide, AJP001, that possesses both a mouse T-cell epitope and adjuvant action. Direct conjugation to the antigen is useful for peptide vaccines without the addition of adjuvants. In this study, the efficacy of an angiotensin (Ang) II and AJP001-conjugated peptide vaccine (AJ-Ang II) was evaluated in mice. Methods The anti-Ang II antibody titer was measured in Balb/C mice following three injections of AJ-Ang II at 2-week intervals. SBP was measured during vaccination of Balb/C mice treated with Ang II infusion (1 μg/kg per min). Results AJ-Ang II treatment resulted in an increase in the anti-Ang II antibody titer in a dose-dependent manner without the addition of adjuvants. In the analysis of the humoral immune response, AJ-Ang II mainly elicited IgG1 antibodies and IL-4 and IL-10 production, as measured by an enzyme-linked immune absorbent spot assay, which suggests the induction of a Th2 response. Importantly, cotreatment with purified antibodies attenuated Ang II-induced extracellular signal-regulated kinase phosphorylation and nuclear factor (NF)-κB activation in cultured vascular smooth muscle cells. The SBP in immunized mice was significantly lower than that in nonimmunized mice (135.9 ± 8.5 vs. 154.9 ± 16.8 mmHg, P = 0.02). Furthermore, Ang II-induced perivascular fibrosis in the heart was significantly attenuated in immunized mice, which also exhibited decreased mRNA expression of collagen I/III and transforming growth factor-β. Conclusion AJ-Ang II may be a simple and useful therapeutic peptide vaccine without the addition of any adjuvants.

Objective: Aortic dissection is a life-threatening disease. At present, the only therapeutic strategies available are surgery and antihypertensive drugs. Moreover, the molecular mechanisms underlying the onset of aortic dissection are still unclear. We established a novel aortic dissection model in mice using pharmacologically induced endothelial dysfunction. We then used the Japanese Adverse Drug Event Report database to investigate the role of pitavastatin in preventing the onset of aortic dissection. Methods and results: To induce endothelial dysfunction, Nω-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, was administered to C57BL/6 mice. Three weeks later, angiotensin II (Ang II) and β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, were administered with osmotic mini-pumps. False lumen formation was used as the pathological determinant of aortic dissection. The incidences of aortic dissection and death from aneurysmal rupture were significantly higher in the Nω-nitro-L-arginine methyl ester, Ang II, and BAPN (LAB) group than they were in the Ang II and BAPN (AB) group. Pitavastatin was administered orally to LAB mice. It significantly lowered the incidences of dissection and rupture. It also decreased inflammation and medial degradation, both of which were exacerbated in the LAB group. The Japanese Adverse Drug Event Report database analysis indicated that there were 113 cases of aortic dissection out of 95 090 patients (0.12%) not receiving statins but only six cases out of 16 668 patients receiving statins (0.04%) (odds ratio: 0.30; P=0.0043). Conclusion: Our results suggest that endothelial dysfunction is associated with the onset of aortic dissection and pitavastatin can help prevent this condition.

Fine particulate matter air pollution (PM2.5) and extreme temperatures have both been associated with alterations in blood pressure (BP). However, few studies have evaluated their joint haemodynamic actions among individuals at high risk for cardiovascular events.We assessed the effects of short-term exposures during the prior week to ambient PM2.5 and outdoor temperature levels on resting seated BP among 2078 patients enrolling into a cardiac rehabilitation programme at the University of Michigan (from 2003 to 2011) using multiple linear regression analyses adjusting for age, sex, BMI, ozone and the same-day alternate environmental factor (i.e. PM2.5 or temperature).Mean PM2.5 and temperature levels were 12.6 ± 8.2 μg/m and 10.3 ± 10.4°C, respectively. Each standard deviation elevation in PM2.5 concentration during lag days 4-6 was associated with significant increases in SBP (2.1-3.5 mmHg) and DBP (1.7-1.8 mmHg). Conversely, higher temperature levels (per 10.4°C) during lag days 4-6 were associated with reductions in both SBP (-3.6 to -2.3 mmHg) and DBP (-2.5 to -1.8 mmHg). There was little evidence for consistent effect modification by other covariates (e.g. demographics, seasons, medication usage).Short-term exposures to PM2.5, even at low concentrations within current air quality standards, are associated with significant increases in BP. Contrarily, higher ambient temperatures prompt the opposite haemodynamic effect. These findings demonstrate that both ubiquitous environmental exposures have clinically meaningful effects on resting BP among high-risk cardiac patients.

Objectives: Although mortality rate due to acute myocardial infarction (AMI) has been extremely improved by the development of early reperfusion therapy, chronic heart failure following AMI is still clinically major issue. We previously demonstrated the level of periostin increased significantly following ischemia. Periostin alternative splicing variant 1 (Pn 1) over-expression resulted in ventricular dilation with enhanced interstitial collagen deposition in rat AMI model. However, the role of alternative splicing variants of periostin is still unclear. Methods: We employed neutralizing antibody (PnAb) that selectively inhibit Pn 1 by blockade of exon-17 and tested in rat AMI model by injecting once a week (200ug ip) throughout experiments. Results: Administration of PnAb resulted in a significant decrease in infarcted and fibrotic area of myocardium preventing ventricular wall thinning and dilatation. Moreover, surviving myocytes in ischemic area was significantly larger than that of control IgG group. Inhibition of fibrosis by PnAb was associated with a significant decrease in gene expression of fibrotic markers such as collagen I, collagen III, and TGF-β1. Importantly, the number of α-SMA positive myofibroblasts was significantly reduced in the heart treated with PnAb, while cardiomyocyte proliferation and angiogenesis were comparable in both IgG and PnAb group. Additionally, the level of Pn 1 expression was correlated significantly with the severity of AMI. In vitro study revealed that Pn 1, but not Pn 2 or 4, inhibited fibroblast and myocyte attachment, leading to myocyte death which might account for cell slippage observed during cardiac remodeling. Conclusion: Specific inhibition of Pn exon-17 by neutralizing antibody without suppressing other Pn variants might offer a new class of medication for the

Objective Diabetes mellitus (DM), characterized by the premature development of microvascular and macrovascular disease, shows a loss of vasodilatory properties of resistance vessels. However, the mechanisms of endothelial dysfunction in diabetes have not yet been clarified. Hepatocyte growth factor (HGF) in vascular cells was down-regulated by high glucose levels, potentially accelerating the endothelial dysfunction in DM. In this study, the serum HGF level was measured to investigate further the role of HGF in DM. Methods Tissue and circulating HGF levels were measured in the KKA y mouse, a rodent model of non-insulin-dependent diabetes mellitus (NIDDM), and lean C57 BL control mice. Then, serum HGF concentrations were measured in NIDDM patients without liver, kidney or lung damage. For the study of serum HGF concentration, 30 normotensive and age-matched 58 DM patients were studied. The 58 DM patients were divided into 26 patients without hypertension and 32 patients with hypertension [22 patients without hypertensive complications (WHO I) and 10 patients with hypertensive complications (WHO II + III)]. Results The serum HGF concentration in KKA y mice was significantly lower than that in control mice (P< 0.01), at 14 weeks of age when they exhibit features of diabetes. Similarly, tissue HGF concentrations in the heart and kidney were decreased significantly in KKA y mice compared with control C57 BL mice (P< 0.05). The serum HGF concentration showed a significant negative correlation with hemoglobin (Hb) A ic concentration (P< 0.01, r= -0.41). Since the serum HGF concentration is a potential index of the severity of hypertension, the serum levels of HGF in DM patients without and with hypertension were examined. The serum HGF concentration in DM patients without hypertension was significantly lower than that in normal subjects (P