Signal transduction of reactive oxygen species and mitogen-activated protein kinases in cardiovascular disease

Reactive oxygen species (ROS), generated by reduction-oxidation (redox) reactions, have been recognized as important chemical mediators that regulate signal transduction. It has been reported that increase in ROS generation may relate to a risk for cardiovascular diseases such as atherosclerosis, angina pectoris, and myocardial infarction. Therefore, understanding the ROS-generating biological processes and ROS-induced intracellular signaling will be informative to gain insights into the pathogenesis of these diseases. In this review, we focus on the sources and reactions of ROS in the cardiovascular system and the role of mitogen-activated protein (MAP) kinase pathway in redox-mediated signal transduction. Clinical implications of ROS and MAP kinase are then described to provide insight into the pathogenesis of various redox-sensitive cardiovascular diseases. The pathways responsible for ROS generation in the cardiovascular system may provide novel therapeutic targets

オルメサルタンは、JNK及びp38シグナル経路を抑制することで、周期的機械的伸展による培養大動脈平滑筋細胞死を抑制する

Acute aortic dissection (AAD) is a life-threating disease; however, there is almost no effective pharmacotherapy for it. An increase in c-Jun N-terminal kinase (JNK) phosphorylation and smooth muscle cell (SMC) apoptosis is observed tissues in patients with AAD. Therefore, we hypothesized that an acute rise in blood pressure leads to SMC death through phosphorylation of JNK or p38, which may cause AAD. We investigated the influence of cyclic mechanical stretch, which mimics an acute increase in blood pressure, on cultured rat aortic SMCs (RASMCs) and examined the changes in JNK and p38 phosphorylation. Further, we investigated the effect of olmesartan, an angiotensin II receptor blocker, on stretch-induced RASMC death. We found that mechanical stretch-induced RASMC death in a time-dependent manner, which correlated with the phosphorylation of JNK and p38. Olmesartan inhibited RASMC death and the phosphorylation of JNK and p38. JNK and p38 inhibitors reversed stretch-induced RASMC death. These results suggest that acute mechanical stretch causes JNK and p38 phosphorylation, which may result in SMC death leading to aortic dissection. Olmesartan may be used for pharmacotherapy to prevent aortic dissection, independent of its blood pressure-lowering effect, through its inhibition of JNK and p38 phosphorylation.博士（医学）・甲第627号・平成27年3月16日Copyright © 2014 Japanese Pharmacological Society. Production and hosting by Elsevier B.V

Possible role of bradykinin on stimulus-secretion coupling in adrenal chromaffin cells

Nonapeptide bradykinin is known to be a central nervous system neurotrans-mitter and to play a role in regulation of neuronal function. However, few details are known of the function of its peptide on stimulus-secretion coupling in neuronal cells. In this article, the role of bradykinin on catecholamine biosynthesis, secretion and Ca2+movement in adrenal chromaffin cells as a model for catecholamine-containing neurons are examined. Bradykinin receptors are classified as B1 and B2 receptor subtypes. These receptors are present on the adrenal chromaffin cell membrane. Bradykinin increases the influx of Ca2+ and the turnover of phosphoinositide through the stimulation of bradykinin B2 receptor. The secretion of catecholamine from the cells is initiated by the raise of [Ca2+]i. An increase in [Ca2+]i and production of diacylglycerol stimulate the activation of calcium-dependent protein kinases. These kinases stimulate the activation of tyrosine hydroxylase, a rate-limiting enzyme in the biosynthesis of catecholamine. Otherwise, bradykinin increases Ca2+ efflux from the cells through the stimulation of the bradykinin-B2 receptor. This action may be explained by an extracellular Na+-dependent mechanism, probably through acceleration of Na+/Ca2+ exchange. It is interesting that bradykinin, which stimulates the biosynthesis and secretion of catecholamine in adrenal chromaffin cells, plays a role in the termination of calcium-signal transduction through the stimu-lation of Ca2+ efflux from the cells

ヒト サイタイ ジョウミャク ナイヒ サイボウ HUVEC ニオケル Lysophosphatidylcholine LPC シゲキ ニヨル VEGF レセプター ノ トランス アクチベーション

One of the major lipid components of oxidized low density lipoprotein, lysophosphatidylcholine （LPC） is involved in numerous biological processes as a bioactive lipid molecule and has been shown to be involved in the progression of atherosclerosis. As counter-ligands, G２A and GPR４ were identified with high binding affinity for LPC that are belonging to orphan G-protein-coupled receptors （GPCRs） at plasma membranes. Although several GPCR ligands transactivate receptor tyrosine kinases （RTKs）, such as epidermal growth factor receptor, transactivation of RTK by LPC has not yet been reported. Here we observed for the first time that LPC treatment induces tyrosyl phosphorylation of vascular endothelial growth factor （VEGF） receptor２ （fetal liver kinase-１／kinase-insert domain-containing receptor, Flk-１／KDR） in human umbilical vein endothelial cells （HUVEC）. VEGF receptor tyrosine kinase inhibitors, SU１４９８ and VTKi inhibited Flk-１／KDR transactivation by LPC. Furthermore, we examined the effect of the Src family kinases inhibitors, Herbimycin A and PP２ on LPC-induced Flk-１／KDR transactivation. Herbimycin A and PP２ inhibited Flk-１／KDR transactivation in HUVEC, suggesting that c-Src is involved in LPC-induced Flk-１／KDR transactivation. Kinase-inactive （KI） Src transfection also inhibited LPC-induced Flk-１／KDR transactivation. In addition, LPC activated extracellular signal-regulated kinase１／２ and Akt, which are downstream effectors of Flk-１／KDR, and these were inhibited by SU１４９８，VTKi, Herbimycin A, PP２ and KI Src transfection in HUVEC. LPC-mediated HUVEC proliferation was shown to be secondary to transactivation because it was suppressed by SU１４９８，VTKi, Herbimycin A, PP２and KI Src transfection. It is concluded that c-Src-mediated Flk-１／KDR transactivation by LPC may have important implications for the progression of atherosclerosis

Accuracy of ultrawide-field fundus ophthalmoscopy-assisted deep learning for detecting treatment-naïve proliferative diabetic retinopathy

Purpose We investigated using ultrawide-field fundus images with a deep convolutional neural network (DCNN), which is a machine learning technology, to detect treatment-naïve proliferative diabetic retinopathy (PDR). Methods We conducted training with the DCNN using 378 photographic images (132 PDR and 246 non-PDR) and constructed a deep learning model. The area under the curve (AUC), sensitivity, and specificity were examined. Result The constructed deep learning model demonstrated a high sensitivity of 94.7% and a high specificity of 97.2%, with an AUC of 0.969. Conclusion Our findings suggested that PDR could be diagnosed using wide-angle camera images and deep learning

Effect of endothelin-1 (1-31) on the renal resistance vessels

Human chymase produces not only angiotensin II but also endothelin(ET)-1(1-31). We previously reported that ET-1(1-31) had several biological activities in vascular smooth muscle cells. In this study, we investigated the vasoconstrictor effect of ET-1(1-31) on the renal resistance vessels using in vitro micro perfused rabbit afferent and efferent arterioles.ET-1(1-31) decreased the lumen diameter of the afferent and efferent arterioles dose-dependently.ET-1(1-31)-induced afferent arteriolar vasoconstriction was not affected by phosphoramidon, an ET converting enzyme inhibitor. ET-1(1-31)-induced renal arteriolar vasoconstriction was inhibited by BQ123, an ETA receptor inhibitor, but not by BQ788, an ETB receptor inhibitor. These results suggest that ET-1(1-31)-induced renal arteriolar vasoconstriction may be mediated by ETA-like receptors

A safe combined nephrectomy and right lobectomy using the liver hanging maneuver for huge renal cell carcinoma directly invading the right lobe of the liver: report of a case

We herein discuss a patient who underwent simultaneous combined right nephrectomy and right lobectomy of the liver. A 64-year-old male was diagnosed with a huge right renal cell carcinoma (RCC), 13 cm in diameter, which was invading directly into the right hepatic lobe. This type of RCC has been rarely reported, and an anterior approach using the liver hanging maneuver was extremely useful during hepatic parenchymal dissection. The liver parenchymal dissection was performed prior to mobilization of the liver, because the mobilization of the right lobe of the liver was impossible. During the hepatic parenchymal resection, the liver was suspended with the tape and transected, and thereafter, retroperitoneal dissection, nephrectomy and right lobectomy of the liver were completed. The patient was discharged from the hospital on the 12th postoperative day with an uneventful clinical course. The anterior approach using the liver hanging maneuver during hepatic parenchymal resection can be safe and feasible for huge RCC invading the right hepatic lobe

Effect of evodiamine on catecholamine secretion from bovine adrenal medulla

The effect of evodiamine on catecholamine secretion from bovine adrenal medulla was investigated. Evodiamine, a bioactive component isolated from dry unripened fruit of Evodia rutaecarpa Bentham, was found to stimulate the secretion of catecholamine from perfused bovine adrenal medulla at a concentration of 10 μM and its effect persisted for at least 30 min. This stimulatory effect of evodiamine was abolished by omission of Ca2+ from the perfusion fluid. Evodiamine (0.1-10 μM) markedly enhanced the secretion of catecholamine from the adrenal medulla induced by acetylcholine (100 μM) or high K+(56 mM). The secretion of catecholamine was promptly enhanced by acetylcholine or high K+, but returned to the control level on treatment for 20 min. However, when evodiamine was added to the perfusion fluid after acetylcholine or high K+ stimulation for 10 min, the secretion of catecholamine again increased greatly. These results indicate that evodiamine not only stimulated the secretion of catecholamine from bovine adrenal medulla but also reversed insensitivity of these cells to acetylcholine or high K+ stimulation

Adenosine receptors in the isolated rabbit afferent and efferent arterioles

Adenosine has been noted as one of the endogenous modulators of renal hemodynamics. Renal hemodynamic was mainly regulated by two resistance vessels, the afferent arteriole and efferent arteriole. However, there is still no consensus as to the intrarenal vascular action site of adenosine. In this study, we examined the direct effect of adenosine on the isolated microperfused rabbit afferent and efferent arterioles. Adenosine decreased the lumen diameter of microperfused afferent arterioles dose-dependently (Control : 14.35±0.97μm, adenosine 10-7M : 12.73±1.40μm, 10-6M : 8.18±1.21μm, 10-5M : 4.33±1.16μm, n=6). Adenosine increased the lumen diameter of adenosine A1 antagonist, 8-(normantan-3-yl)-1,3-dipropylxanthin (KW-3902), pretreated-microperfused afferent arterioles preconstricted by norepinephrine. Pretreatment with adenosine A2 antagonist, (E)-1,3,-dipropyl-8-(3,4-dimethoxystyryl)-7-methylxanthin (KF-7837), enhanced adenosine induced-afferent arteriolar vasoconstrictor effect. Adenosine did not change the lumen diameter of microperfused efferent arterioles, but adenosine increased the lumen diameter of norepinephrine preconstricted-microperfused efferent arterioles. The present data suggest that the afferent arterioles possesses both adenosine A1 and A2 receptors and the efferent arterioles possesses predominantly adenosine A2 receptors at least in the rabbit kidney