Ageing is the predominant risk factor for cardiovascular diseases and contributes to a significantly worse outcome in patients with acute myocardial infarction. MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing. We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.

Background-Cell therapy is a promising option to improve functional recovery after ischemia. Several subsets of bone marrow-derived cells were shown to reduce infarct size and increase ejection fraction in experimental models of ischemia. The mechanisms underlying the functional improvement are diverse and have been shown to include paracrine effects of the injected cells, as well as a variable degree of differentiation to endothelial cells, pericytes, smooth muscle, and cardiac muscle. Methods and Results-To elucidate the true nature of such plasticity and contribution to recovery, we engineered vectors that encoded inducible suicide genes under the control of endothelium (endothelial nitric oxide synthase)-, smooth muscle (SM22␣)-, and cardiomyocyte (␣-MHC)-specific promoters, thereby allowing selective depletion of the individual cell lineage acquired by the transplanted undifferentiated bone marrow-derived cells. Lentivirally delivered thymidine kinase, which converts the prodrug ganciclovir into a cytotoxic agent, was used to selectively eliminate cells 2 weeks after transplantation of bone marrow mononuclear cells in an acute myocardial infarction model. We demonstrate that elimination of transplanted endothelium-committed or SM22␣-expressing cells, but not cardiaccommitted cells, induced a significant deterioration of ejection fraction. Moreover, elimination of endothelial nitric oxide synthase-expressing cells 2 weeks after injection reduced capillary and arteriole density. Key Words: cell therapy Ⅲ endothelial nitric oxide synthase Ⅲ vasculature Ⅲ angiogenesis-inducing agents C ell therapy is a promising option to restore cardiac function after ischemia or during heart failure. Various subsets of adult bone marrow-derived or tissue-resident progenitor cells were shown to augment the recovery of cardiac function after ischemia in experimental models. Most clinical studies to date have been performed with total bone marrow mononuclear cells (BMCs), which comprise hematopoietic progenitor cells, mesenchymal stem cells, and monocytes. Treatment of patients with acute myocardial infarction with BMCs induced a modest increase in ejection fraction and beneficially interfered with left ventricular remodeling processes in most but not all studies. 1 However, the mechanisms underlying the functional improvement are discussed controversially, and the long-term engraftment and differentiation were variable between the studies. Because cardiac function was improved in some studies even in the absence of significant long-term engraftment and differentiation of the injected cells, it has been speculated that paracrine mechanisms might be responsible for the therapeutic benefit achieved by bone marrow-derived cells (for review, see Gnecchi et al 2 ). Meanwhile, various studies confirmed that progenitor cells release paracrine factors that modulate angiogenesis, cardiomyocyte apoptosis, fibrosis, and inflammation, and various cytokines and growth factors have been identified in progenitor cells that mechanistically cont...

BackgroundThe global EINSTEIN DVT and PE studies compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) with enoxaparin/vitamin K antagonist therapy and demonstrated non-inferiority for efficacy and superiority for major bleeding. Owing to differences in targeted anticoagulant intensities in Japan, Japanese patients were not enrolled into the global studies. Instead, a separate study of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in Japanese patients was conducted, which compared the Japanese standard of care with a reduced dose of rivaroxaban.MethodsWe conducted an open-label, randomized trial that compared 3, 6, or 12 months of oral rivaroxaban alone (10 mg twice daily or 15 mg twice daily for 3 weeks followed by 15 mg once daily) with activated partial thromboplastin time-adjusted intravenous unfractionated heparin (UFH) followed by warfarin (target international normalized ratio 2.0; range 1.5–2.5) in patients with acute, objectively confirmed symptomatic DVT and/or PE. Patients were assessed for the occurrence of symptomatic recurrent venous thromboembolic events or asymptomatic deterioration and bleeding.ResultsEighty-one patients were assigned to rivaroxaban and 19 patients to UFH/warfarin. Three patients were excluded because of serious non-compliance issues. The composite of symptomatic venous thromboembolic events or asymptomatic deterioration occurred in 1 (1.4%) rivaroxaban patient and in 1 (5.3%) UFH/warfarin patient (absolute risk difference, 3.9% [95% confidence interval, -3.4–23.8]). No major bleeding occurred during study treatment. Clinically relevant non-major bleeding occurred in 6 (7.8%) patients in the rivaroxaban group and 1 (5.3%) patient in the UFH/warfarin group.ConclusionsThe findings of this study in Japanese patients with acute DVT and/or PE suggest a similar efficacy and safety profile with rivaroxaban and control treatment, consistent with that of the worldwide EINSTEIN DVT and PE program.Trial registrationClinicaltrials.gov: NCT01516840 and NCT01516814.Electronic supplementary materialThe online version of this article (doi:10.1186/s12959-015-0035-3) contains supplementary material, which is available to authorized users.

Abstract-The purpose of this study was to investigate the effect of hepatocyte growth factor (HGF) on the pathogenesis of cardiac fibrosis induced by pressure overload in mice. Although cardiac fibrosis is attributed to excess pathological deposition of extracellular matrix components, the mechanism remains unclear. Recent reports revealed that ␣-smooth muscle actin-expressing myofibroblasts are primarily responsible for fibrosis. It is believed that myofibroblasts are differentiated from resident fibroblasts, whereas the transformation of vascular endothelial cells into myofibroblasts, known as endothelial-mesenchymal transition, has been suggested to be intimately associated with perivascular fibrosis. Thus, we hypothesized that HGF prevents cardiac fibrosis by blocking these pathways. We analyzed the pressureoverloaded HGF-transgenic mouse model made by transverse aortic constriction. Human coronary artery endothelial cells and human cardiac fibroblasts were examined in vitro after being treated with transforming growth factor-␤1 or angiotensin II with or without HGF. The amount of cardiac fibrosis significantly decreased in pressure-overloaded HGF-transgenic mice compared with pressure-overloaded nontransgenic controls, particularly in the perivascular region. This was accompanied by a reduction in the expression levels of fibrosis-related genes and by significant preservation of echocardiographic measurements of cardiac function in the HGF-transgenic mice (PϽ0.05). The survival rate 2 months after transverse aortic constriction was higher by 45% (PϽ0.05). HGF inhibited the differentiation of human coronary artery endothelial cells into myofibroblasts induced by transforming growth factor-␤1 and the phenotypic conversion of human cardiac fibroblasts into myofibroblasts. We conclude that HGF reduced cardiac fibrosis by inhibiting endothelialmesenchymal transition and the transformation of fibroblasts into myofibroblasts. 1 The number of cardiovascular deaths has been reduced, but in spite of a marked development in recent devices and medicines, cardiovascular disease still impacts the mortality rate in almost all nations.2 Cardiac fibrosis is often present in end-stage heart failure and is caused by various factors, such as ischemia, 3 pressure overload, 4 and cardiomyopathy, 5 so antifibrotic therapy is believed to be beneficial in preventing heart failure. Although fibrosis, which is attributed to an excess deposition of extracellular matrix (ECM) components, is one of the most common pathological changes found in various organs, including the heart, the detailed mechanism remains unclear. It is worth noting that myofibroblasts are characterized by ␣-smooth muscle actin (␣-SMA) expression and appear to play a major role in the pathogenesis of fibrosis by secreting numerous cytokines, growth factors, and ECM proteins. 6 Myofibroblasts were originally thought to be differentiated from resident fibroblasts activated by acute or chronic stimuli, such as myocardial infarction and pressure overload. On the other ...

Abstract-Our previous study demonstrated that periostin, an extracellular matrix protein, plays an important role in left ventricular remodeling through the inhibition of cell-cell interactions. Because the gene regulation of periostin has not yet been examined, we focused on the effects of angiotensin (Ang) II and mechanical stretch, because Ang II and mechanical stretch are related to cardiac remodeling after myocardial infarction. First, we examined the effects of Ang II on periostin in myocytes and fibroblasts in vitro. Ang II significantly increased periostin through phosphatidylinositol 3-kinase, c-Jun N-terminal kinase, p38, and extracellular signal-regulated kinase 1/2 pathways in myocytes and fibroblasts (PϽ0.05). On the other hand, mechanical stretch also significantly increased periostin expression (PϽ0.05). This increase was inhibited partially, but significantly, by an Ang II receptor blocker, valsartan, and inhibited almost completely by valsartan with the neutralization antibodies for transforming growth factor-␤ and platelet-derived growth factor-BB (PϽ0.05). Therefore, we further examined periostin expression in vivo. Periostin expression was significantly increased in infarcted myocardium (PϽ0.05), and treatment with valsartan significantly attenuated it at 4 weeks after myocardial infarction (PϽ0.05), accompanied by a significant improvement in cardiac dysfunction (PϽ0.05). Overall, the present study demonstrated that Ang II, as well as mechanical stretch, stimulated periostin expression in both cardiac myocytes and fibroblasts, whereas valsartan significantly attenuated the increase in periostin expression. The inhibition of periostin by valsartan might especially contribute to its beneficial effects on cardiac remodeling after myocardial infarction. Key Words: angiotensin II type 1 receptor blockers Ⅲ myocardial infarction Ⅲ adhesions Ⅲ fibrosis Ⅲ ventricular remodeling C ardiac remodeling after myocardial infarction (MI) results in ventricular dysfunction, which contributes to a poor outcome and high mortality. 1 The use of angiotensin (Ang)-converting enzyme inhibitors in patients with MI has improved survival and reduced the rates of major cardiovascular events, 2 and Ang II receptor blockers (ARBs) were expected to prevent cardiac remodeling, like Ang-converting enzyme inhibitors. The Valsartan in Acute Myocardial Infarction Trial demonstrated that an ARB, valsartan, was as effective as a proven regimen of an Ang-converting enzyme inhibitor captopril in improving survival and reducing cardiovascular mortality in patients who suffered an MI. 3,4 Treatment with captopril or valsartan resulted in similar changes in cardiac volume and ejection fraction after MI, 3 whereas treatment with captopril after MI significantly reduced left ventricular (LV) enlargement. 2 On the other hand, periostin is a novel secreted and putative soluble extracellular matrix protein 5 and is known to be expressed in bone and to a lesser extent in lung, kidney, and heart valves but is not found in normal blood vess...