Histone methylation and demethylation are implicated in the transient and sustained activation of the interleukin-1β gene in murine macrophages.

Macrophages play a crucial role in the development of atherosclerosis. To explore the mechanism by which macrophages attain a proinflammatory phenotype for a sustained period, we stimulated macrophages with lipopolysaccharide (LPS) and interferon-γ (IFN-γ) and measured the interleukin-1β (IL-1β) expression. The IL-1β expression increased transiently, and its expression lasted for, at least, 1 week after the cessation of LPS and IFN-γ stimulation.

Endogenous Interleukin-1β Is Implicated in Intraplaque Hemorrhage in Apolipoprotein E Gene Null Mice.

Background: Intraplaque hemorrhage (IPH) has been implicated in plaque instability and rupture in atherosclerotic lesions, although the mechanisms by which IPH progresses remain largely unknown. In this study, apolipoprotein E-deficient mice with carotid artery ligation and cuff placement around the artery were used, and pro-inflammatory cytokines that are implicated in IPH were analyzed.

Methods and results: The expression of interleukin-1β (IL-1β) increased significantly following cuff placement compared with mice with carotid artery ligation alone.

Therapeutic Effects of Mesenchymal Stem Cell-Derived Exosomes in Cardiovascular Disease.

Mesenchymal stem cells (MSCs) are multipotent stem cells that reside in various organs. They have the capacity to differentiate into various cell types, including cardiomyocytes, vascular endothelial cells, and vascular smooth muscle cells. Among the various MSCs, bone marrow-derived MSCs (BMMSCs) have been widely used for treating acute myocardial infarction (AMI) and ischemic heart failure (IHF) in preclinical and clinical studies.

Stem cell-derived exosomes as a therapeutic tool for cardiovascular disease.

Mesenchymal stem cells (MSCs) have been used to treat patients suffering from acute myocardial infarction (AMI) and subsequent heart failure. Although it was originally assumed that MSCs differentiated into heart cells such as cardiomyocytes, recent evidence suggests that the differentiation capacity of MSCs is minimal and that injected MSCs restore cardiac function via the secretion of paracrine factors. MSCs secrete paracrine factors in not only naked forms but also membrane vesicles including exosomes containing bioactive substances such as proteins, messenger RNAs, and microRNAs.

The angiotensin II receptor antagonist, losartan, enhances regulator of G protein signaling 2 mRNA expression in vascular smooth muscle cells of Wistar rats.

Angiotensin II (Ang II) reportedly enhances regulator of G-protein signaling 2 (RGS2), thus making a negative feedback loop for Ang II signal transduction. However, few studies have reported whether Ang II receptor (ATR) antagonists influence RGS2 mRNA expression. We investigated RGS2 mRNA expression when Ang II binding to ATR was blocked with Ang II subtype-1 receptor (AT1R) blockers using vascular smooth muscle cells from the thoracic aorta of male Wistar rats.

Impaired response of regulator of Gαq signaling-2 mRNA to angiotensin II and hypertensive renal injury in Dahl salt-sensitive rats.

Dahl salt-sensitive (Dahl S) rats are prone to salt-dependent hypertension with severe organ damage, including stroke, cardiac failure and renal insufficiency. The mechanism for this susceptibility to kidney injury has not been elucidated. The present study proposed that an upregulation of intracellular signaling of angiotensin II (Ang-II) is responsible for the susceptibility to hypertensive kidney injury in Dahl S rats.

Neuromedin B Restores Erectile Function by Protecting the Cavernous Body and the Nitrergic Nerves from Injury in a Diabetic Rat Model.

Erectile dysfunction (ED) is a major health problem worldwide and affects approximately 75% of diabetic patients, likely due to severely damaged cavernous body. While screening for cytokines produced by adipose tissue-derived stem cells, we detected neuromedin B (NMB). To explore a potential treatment option for ED, we examined whether NMB was capable of restoring erectile function.

Senescent Cells Impair Erectile Function through Induction of Endothelial Dysfunction and Nerve Injury in Mice.

Erectile dysfunction (ED) is a major health problem, particularly in the elderly population, which is rapidly increasing. It is necessary to elucidate the mechanism by which ED occurs in the elderly. Cellular senescence is commonly detected in old tissues, and it is well known that senescent cells not only withdraw from the cell cycle but also remain viable and actively produce a variety of cytokines.

Chronic kidney disease and erectile dysfunction.

Erectile dysfunction (ED) is a common condition among male chronic kidney disease (CKD) patients. Its prevalence is estimated to be approximately 80% among these patients. It has been well established that the production of nitric oxide from the cavernous nerve and vascular endothelium and the subsequent production of cyclic GMP are critically important in initiating and maintaining erection.

Adipose-derived stem cells stimulate reendothelialization in stented rat abdominal aorta.

Background: Although drug-eluting stents (DES) have been widely used for the treatment of coronary artery disease, they potentially increase the risk of late thrombosis. It is, therefore, desirable to establish a strategy to stimulate reendothelialization. Endothelial injury models have been widely used to analyze the mechanisms of coronary restenosis.

A useful method of identifying of miRNAs which can down-regulate Zeb-2.

Background: Although identification of the target mRNAs of micro RNAs (miRNAs) is essential to understanding their function, the low complementarity between miRNAs and their target mRNAs has complicated this process. In this study, we sought to identify miRNAs which reduce the expression of the transcription factor Zeb-2, a transcriptional repressor of E-cadherin which is known to be down regulated by members of the miR-200 family (miR-200a,b,c miR-429, and miR-141).

Findings: We first used a computational target predicting system to identify 82 candidate miRNAs which bound the 3'UTR region of the Zeb-2 mRNA.

Oncogene- and oxidative stress-induced cellular senescence shows distinct expression patterns of proinflammatory cytokines in vascular endothelial cells.

Senescent cells are metabolically active and produce a variety of proinflammatory cytokines. It was previously reported that atherosclerotic plaques contain senescent cells, suggesting that senescence may contribute to the progression of atherosclerosis. In this study, we induced cellular senescence in vascular endothelial cells (VECs) using hydrogen peroxide (H₂O₂) or an adenovirus that expresses a constitutively active mutant of Ras (AdRas12V) and studied the expression of cytokines.

Adrenomedullin and angiopoietin-1 additively restore erectile function in diabetic rats: comparison with the combination therapy of vascular endothelial growth factor and angiopoietin-1.

Introduction: Erectile dysfunction (ED) is a major health problem. We have shown that adrenomedullin (AM) restores erectile function in diabetic rats.

Aim: The aim of this study is to explore a better treatment for ED, we examined whether combination of AM and angiopoietin-1 (Ang-1) was more effective to treat ED than treatment with AM alone or Ang-1 alone.

Angiopoietin-1 mediates adipose tissue-derived stem cell-induced inhibition of neointimal formation in rat femoral artery.

Background:  Adipose tissue-derived stem cells (ASC) produce a variety of cytokines that potentially mediate the proangiogenic and antiapoptotic effects of the ASC. We examined whether ASC produced angiopoietin-1 (Ang1) and whether Ang1 functionally mediated ASC-induced suppression of neointimal formation.

Methods And Results:  Ang1 production was measured by enzyme-linked immunosorbent assay.

Renoprotective effect of erythropoietin in ischemia/reperfusion injury: possible roles of the Akt/endothelial nitric oxide synthase-dependent pathway.

Objectives: It has been reported that erythropoietin protects the kidneys from ischemia/reperfusion injury. In the present study, we examined the role of Akt and endothelial nitric oxide synthase in the protective effect of erythropoietin on ischemia/reperfusion injury of the kidney.

Methods: Erythropoietin was injected in the peritoneal space of ICR mice after ischemia/reperfusion injury and its effect was assessed by measuring blood urea nitrogen and creatinine, and by histological analysis.

Adrenomedullin mediates adipose tissue-derived stem cell-induced restoration of erectile function in diabetic rats.

Introduction: Erectile dysfunction (ED) is a major health problem. It is known that diabetic patients are more refractory to common treatments for ED.

Aim: To explore the better treatment for ED, we examined the effects of adipose-derived stem cells (ASC) on ED using a diabetic rat model.

miR-200b precursor can ameliorate renal tubulointerstitial fibrosis.

Members of the miR-200 family of micro RNAs (miRNAs) have been shown to inhibit epithelial-mesenchymal transition (EMT). EMT of tubular epithelial cells is the mechanism by which renal fibroblasts are generated. Here we show that miR-200 family members inhibit transforming growth factor-beta (TGF-beta)-induced EMT of tubular cells.

Diagnosis and treatment of endothelial dysfunction in cardiovascular disease.

Vascular endothelial dysfunction reflected by reduced nitric oxide (NO) availability is certainly the causative factor or promoting mechanism of arteriosclerosis. It is necessary to detect endothelial dysfunction at an early stage using appropriate methods, and to choose a treatment for the recovery of endothelial function. There are nonpharmacological and pharmacological therapies to attain endothelial repair.

Adipose tissue-derived stem cells inhibit neointimal formation in a paracrine fashion in rat femoral artery.

Subcutaneous adipose tissue contains a lot of stem cells [adipose-derived stem cells (ASCs)] that can differentiate into a variety of cell lineages. In this study, we isolated ASCs from Wistar rats and examined whether ASCs would efficiently differentiate into vascular endothelial cells (ECs) in vitro. We also administered ASCs in a wire injury model of rat femoral artery and examined their effects.

Progression of renal dysfunction in patients with cardiovascular disease.

It has been established that patients with chronic kidney disease (CKD) suffer from frequent cardiovascular events. On the other hand, recent studies suggest that renal damage tends to worsen in patients with cardiovascular diseases (CVD). Although the mechanisms for the cardiorenal association are unclear, the presence of arteriosclerotic risk factors common to both CVD and CKD is important.

Blockade of endogenous proinflammatory cytokines ameliorates endothelial dysfunction in obese Zucker rats.

To study the role of endogenous proinflammatory cytokines in endothelial dysfunction in diabetes, we administered semapimod, an inhibitor of proinflammatory cytokine production, to obese Zucker (OZ) rats, and examined its effect on endothelium-dependent vasorelaxation. Endothelium-dependent vasorelaxation induced by acetylcholine and adrenomedullin (AM) was significantly reduced in OZ rats compared to a control group of lean Zucker rats. Semapimod significantly restored endothelium-dependent vasorelaxation in OZ rats.

Calcineurin is critical for sodium-induced neointimal formation in normotensive and hypertensive rats.

It is well known that excessive intake of sodium chloride (sodium) is a risk factor for cardiovascular disease because it raises blood pressure. However, sodium loading reportedly promotes cardiovascular disease independently of its effect on blood pressure. To examine the mechanisms by which sodium loading promotes vascular inflammation independently of its effect on blood pressure, we examined the role of calcineurin in sodium loading-induced vascular inflammation using a wire injury model of the rat femoral artery.