Kazuhiro Matsuo

Efficient homogeneous acid catalysis of heteropoly acid and its characterization through ether cleavage reactions

Summary A Keggin-type heteropoly acid has revealed high catalytic activities for the cleavage reactions of epoxides, tetrahydrofuran, dibutyl ether and butyl methyl ether with acetic acid, acetic anhydride and butyl acetate in the non-aqueous homogeneous liquid phase at 30–118 °C. The catalytic activities of the heteropoly acid were much higher than those of conventional acid catalysts such as sulfuric acid, p-toluensulfonic acid and boron trifluoride etherate, at the same catalysts concentrations or the same proton concentrations. On the basis of comparative measurements of electrical conductivity, acidity, and softness of anion for the solutions of acid catalysts, the eficcient acid catalysis by heteropoly acid was suggested to be due to the specific properties of the heteropoly anion, which can be characterized by very weak basicity and great softness, togerther with the large size of the polyhedral structure.

CTRP9 Protein Protects against Myocardial Injury following Ischemia-Reperfusion through AMP-activated Protein Kinase (AMPK)-dependent Mechanism

Background: The functional role of the fat-derived plasma protein CTRP9 in ischemic heart disease is unknown. Results: Systemic delivery of CTRP9 reduces myocardial infarct size and apoptosis following ischemia-reperfusion in mice. CTRP9 protects cardiomyocyte from apoptosis through activation of AMP-activated protein kinase (AMPK). Conclusion: CTRP9 prevents acute cardiac ischemic injury via an AMPK-dependent mechanism. Significance: CTRP9 represents a novel target molecule for manipulation of myocardial ischemic injury. Ischemic heart disease is the major cause of death in Western countries. CTRP9 (C1q/TNF-related protein 9) is a fat-derived plasma protein that has salutary effects on glucose metabolism and vascular function. However, the functional role of CTRP9 in ischemic heart disease has not been clarified. Here, we examined the regulation of CTRP9 in response to acute cardiac injury and investigated whether CTRP9 modulates cardiac damage after ischemia and reperfusion. Myocardial ischemia-reperfusion injury resulted in reduced plasma CTRP9 levels and increased plasma free fatty acid levels, which were accompanied by a decrease in CTRP9 expression and an increase in NADPH oxidase component expression in fat tissue. Treatment of cultured adipocytes with palmitic acid or hydrogen peroxide reduced CTRP9 expression. Systemic administration of CTRP9 to wild-type mice, before the induction of ischemia or at the time of reperfusion, led to a reduction in myocardial infarct size following ischemia-reperfusion. Administration of CTRP9 also attenuated myocyte apoptosis in ischemic heart, which was accompanied by increased phosphorylation of AMP-activated protein kinase (AMPK). Treatment of cardiac myocytes with CTRP9 protein reduced apoptosis in response to hypoxia/reoxygenation and stimulated AMPK phosphorylation. Blockade of AMPK activity reversed the suppressive actions of CTRP9 on cardiomyocyte apoptosis. Knockdown of adiponectin receptor 1 diminished CTRP9-induced increases in AMPK phosphorylation and survival of cardiac myocytes. Our data suggest that CTRP9 protects against acute cardiac injury following ischemia-reperfusion via an AMPK-dependent mechanism.

Omentin Prevents Myocardial Ischemic Injury Through AMP-Activated Protein Kinase- and Akt-Dependent Mechanisms

OBJECTIVESnThis study examined the impact of omentin on myocardial injury in a mouse model of ischemia/reperfusion (I/R) and explored its underlying mechanisms.nnnBACKGROUNDnObesity is a major risk factor for ischemic heart disease. Omentin is a circulating adipokine that is down-regulated by obesity.nnnMETHODSnIn patients who underwent successful reperfusion treatment after acute myocardial infarction, cardiac function and perfusion defect were assessed by using scintigraphic images. Mice were subjected to myocardial ischemia followed by reperfusion.nnnRESULTSnThis study found that high levels of plasma omentin were associated with improvement of heart damage and function after reperfusion therapy in patients with acute myocardial infarction. Systemic administration of human omentin to mice led to a reduction in myocardial infarct size and apoptosis after I/R, which was accompanied by enhanced phosphorylation of AMP-activated protein kinase (AMPK) and Akt in the ischemic heart. Fat-specific overexpression of human omentin also resulted in reduction of infarct size after I/R. Blockade of AMPK or Akt activity reversed omentin-induced inhibition of myocardial ischemic damage and apoptosis in mice. In cultured cardiomyocytes, omentin suppressed hypoxia/reoxygenation-induced apoptosis, which was blocked by inactivation of AMPK or Akt.nnnCONCLUSIONSnOur data indicate that omentin functions as an adipokine that ameliorates acute ischemic injury in the heart by suppressing myocyte apoptosis through both AMPK- and Akt-dependent mechanisms.

Adipose-derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation

Obesity is closely associated with the progression of vascular disorders, including atherosclerosis and postangioplasty restenosis. C1q/TNF‐related protein (CTRP) 9 is an adipocytokine that is down‐regulated in obese mice. Here we investigated whether CTRP9 modulates neointimal hyperplasia and vascular smooth muscle cell (VSMC) proliferation in vivo and in vitro. Left femoral arteries of wild‐type (WT) mice were injured by a steel wire. An adenoviral vector expressing CTRP9 (Ad‐CTRP9) or β‐galactosidase as a control was intravenously injected into WT mice 3 d before vascular injury. Delivery of Ad‐CTRP9 significantly attenuated the neointimal thickening and the number of bromode‐oxyuridine‐positive proliferating cells in the injured arteries compared with that of control. Treatment of VSMCs with CTRP9 protein attenuated the proliferative and chemotactic activities induced by growth factors including platelet‐derived growth factor (PDGF)‐BB, and suppressed PDGF‐BB‐stimulated phosphorylation of ERK. CTRP9 treatment dose‐dependently increased cAMP levels in VSMCs. Blockade of cAMP‐PKA pathway reversed the inhibitory effect of CTRP9 on DNA synthesis and ERK phosphorylation in response to PDGF‐BB. The present data indicate that CTRP9 functions to attenuate neointimal formation following vascular injury through its ability to inhibit VSMC growth via cAMP‐dependent mechanism, suggesting that the therapeutic approaches to enhance CTRP9 production could be valuable for prevention of vascular restenosis after angioplasty.—Uemura, Y., Shibata, R., Ohashi, K., Enomoto, T., Kambara, T., Yamamoto, T., Ogura, Y., Yuasa, D., Joki, Y., Matsuo, K., Miyabe, M., Kataoka, Y., Murohara, T., Ouchi, N. Adipose‐derived factor CTRP9 attenuates vascular smooth muscle cell proliferation and neointimal formation. FASEB J. 27, 25–33 (2013). www.fasebj.org

FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism

Ischemic heart disease is one of the leading causes of death. Fibroblast growth factor 21 (FGF21) is a circulating factor with an anti-diabetic property. Skeletal muscle is an important source of FGF21 production. Here, we investigated whether skeletal muscle-derived FGF21 modulates cardiac remodeling in a murine model of myocardial infarction. Myocardial infarction was produced in C57BL/6J wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery (LAD). Adenoviral vectors expressing FGF21 (Ad-FGF21) or control β-galactosidase were intramuscularly injected into mice at 3 days before permanent LAD ligation. Intramuscular injection of Ad-FGF21 increased plasma FGF21 levels in WT mice compared with control. Treatment of WT mice with Ad-FGF21 led to improvement of left ventricular systolic dysfunction and dilatation at 2 weeks after LAD ligation. Ad-FGF21 administration to WT mice also led to enhancement of capillary density in the infarct border zone, and reduction of myocyte apoptosis in the remote zone, which were accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, treatment of WT mice with Ad-FGF21 increased plasma levels of adiponectin, which is a cardioprotective adipokine. The beneficial effects of Ad-FGF21 on cardiac dysfunction and inflammatory response after myocardial infarction were diminished in adiponectin-knockout mice. These data suggest that muscle-derived FGF21 ameliorates adverse cardiac remodeling after myocardial infarction, at least in part, through an adiponectin-dependent mechanism.

Adipose-derived protein omentin prevents neointimal formation after arterial injury

Obesity is highly linked with the development of vascular diseases. Omentin is a circulating adipokine that is downregulated in patients with cardiovascular diseases. In this study, we investigated the role of omentin in regulation of vascular remodeling in response to injury. Wild‐type (WT) mice were treated intravenously with adenoviral vectors encoding human omentin (Ad‐OMT) or control β‐gal and subjected to arterial wire injury. Ad‐OMT treatment reduced the neointimal thickening and the frequencies of bromodeoxyuridine‐positive proliferating cells in injured arteries. Treatment of vascular smooth muscle cells (VSMCs) with human omentin protein at a physiologic concentration led to suppression of growth and ERK phosphorylation after stimulation with various growth factors. Omentin stimulated AMPK signaling in VSMCs, and blockade of AMPK reversed omentin‐mediated inhibition of VSMC growth and ERK phosphorylation. Furthermore, fat‐specific human omentin transgenic (OMT‐TG) mice exhibited reduced neointimal thickening and vascular cell growth following vascular injury. AMPK activation was enhanced in injured arteries in OMT‐TG mice, and administration of AMPK inhibitor reversed the reduction of neointimal hyperplasia in OMT‐TG mice. These data indicate that omentin attenuates neointimal formation after arterial injury and suppresses VSMC growth through AMPK‐dependent mechanisms. Thus, omentin can represent a novel target molecule for the prevention of vascular disorders.—Uemura, Y., Shibata, R., Kanemura, N., Ohashi, K., Kambara, T., Hiramatsu‐Ito, M., Enomoto, T., Yuasa, D., Joki, Y., Matsuo, K., Ito, M., Hayakawa, S., Ogawa, H., Murohara, T., Ouchi, N., Adipose‐derived protein omentin prevents neointimal formation after arterial injury. FASEB J. 29, 141–151 (2015). www.fasebj.org

Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury

AIMSnIt is well-established that exercise diminishes cardiovascular risk, but whether humoral factors secreted by muscle confer these benefits has not been conclusively shown. We have shown that the secreted protein follistatin-like 1 (Fstl1) has beneficial actions on cardiac and endothelial function. However, the role of muscle-derived Fstl1 in proliferative vascular disease remains largely unknown. Here, we investigated whether muscle-derived Fstl1 modulates vascular remodelling in response to injury.nnnMETHODS AND RESULTSnThe targeted ablation of Fstl1 in muscle led to an increase in neointimal formation following wire-induced arterial injury compared with control mice. Conversely, muscle-specific Fstl1 transgenic (TG) mice displayed a decrease in the neointimal thickening following arterial injury. Muscle-specific Fstl1 ablation and overexpression increased and decreased, respectively, the frequency of BrdU-positive proliferating cells in injured vessels. In cultured human aortic smooth muscle cells (HASMCs), treatment with human FSTL1 protein decreased proliferation and migration induced by stimulation with PDGF-BB. Treatment with FSTL1 enhanced AMPK phosphorylation, and inhibition of AMPK abrogated the inhibitory actions of FSTL1 on HASMC responses to PDGF-BB. The injured arteries of Fstl1-TG mice exhibited an increase in AMPK phosphorylation, and administration of AMPK inhibitor reversed the anti-proliferative actions of Fstl1 on the vessel wall.nnnCONCLUSIONnOur findings indicate that muscle-derived Fstl1 attenuates neointimal formation in response to arterial injury by suppressing SMC proliferation through an AMPK-dependent mechanism. Thus, the release of protein factors from muscle, such as Fstl1, may partly explain why the maintenance of muscle function can have a therapeutic effect on the cardiovascular system.

C1q/Tumor Necrosis Factor-Related Protein 9 Protects against Acute Myocardial Injury through an Adiponectin Receptor I-AMPK-Dependent Mechanism.

ABSTRACT Obesity is a risk factor for cardiovascular disease. C1q/tumor necrosis factor-related protein 9 (CTRP9) is an adipokine that is downregulated by obesity. We investigated the role of CTRP9 in cardiac injury with loss-of-function genetic manipulations and defined the receptor-mediated signaling pathway downstream of this adipokine. CTRP9-knockout (CTRP9-KO) mice at the age of 12 weeks were indistinguishable from wild-type (WT) mice under basal conditions. CTRP9-KO mice had exacerbated contractile left ventricle dysfunction following intraperitoneal injection of lipopolysaccharide (LPS) compared to WT mice. Administration of LPS to CTRP9-KO mice also resulted in increased expression of proinflammatory cytokines and oxidative stress markers in the heart compared to WT mice. Likewise, CTRP9-KO mice showed increased myocardial infarct size and elevated expression of inflammatory mediators in ischemic heart following ischemia and reperfusion compared to WT mice. Treatment of cardiac myocytes with CTRP9 protein led to suppression of LPS-induced expression of proinflammatory genes, which was reversed by blockade of AMPK or ablation of adiponectin receptor I (AdipoR1). Systemic delivery of CTRP9 attenuated LPS-induced cardiac dysfunction in WT mice but not in muscle-specific transgenic mice expressing dominant-negative mutant form of AMPK or in AdipoR1-knockout mice. CTRP9 protects against acute cardiac damage in response to pathological stimuli by suppressing inflammatory reactions through AdipoR1/AMPK-dependent mechanisms.

Omentin attenuates atherosclerotic lesion formation in apolipoprotein E-deficient mice

AIMSnObesity is associated with the development of atherosclerosis. We previously demonstrated that omentin is a circulating adipokine that is downregulated in association with atherosclerotic diseases. Here, we examined the impact of omentin on the development of atherosclerosis with gain-of-function genetic manipulations and dissected its potential mechanism.nnnMETHODS AND RESULTSnApolipoprotein E-deficient (apoE-KO) mice were crossed with transgenic mice expressing the human omentin gene (OMT-Tg) mice in fat tissue to generate apoE-KO/OMT-Tg mice. ApoE-KO/OMT-Tg mice exhibited a significant reduction of the atherosclerotic areas in aortic sinus, compared with apoE-KO mice despite similar lipid levels. ApoE-KO/OMT-Tg mice also displayed significant decreases in macrophage accumulation and mRNA expression of proinflammatory mediators including tumour necrosis factor-α, interleukin-6, and monocyte chemotactic protein-1 in aorta when compared with apoE-KO mice. Treatment of human monocyte-derived macrophages with a physiological concentration of human omentin protein led to reduction of lipid droplets and cholesteryl ester content. Treatment with human omentin protein also reduced lipopolysaccharide-induced expression of proinflammatory genes in human macrophages. Treatment of human macrophages with omentin promoted the phosphorylation of Akt. Inhibition of Akt signalling abolished the anti-inflammatory actions of omentin in macrophages.nnnCONCLUSIONnThese data document for the first time that omentin reduces the development of atherosclerosis by reducing inflammatory response of macrophages through the Akt-dependent mechanisms.

C1q/TNF-related protein-1 functions to protect against acute ischemic injury in the heart

Obesity is associated with an increased risk of cardiovascular disease. C1q/TNF‐related protein (CTRP)‐1 is a poorly characterized adipokine that is up‐regulated in association with ischemic heart disease. We investigated the role of CTRP1 in myocardial ischemia injury. CTRP1‐knockout mice showed increased myocardial infarct size, cardiomyocyte apoptosis, and proinflammatory gene expression after I/R compared with wild‐type (WT) mice. In contrast, systemic delivery of CTRP1 attenuated myocardial damage after I/R in WT mice. Treatment of cardiomyocytes with CTRP1 led to reduction of hypoxia‐reoxygenation‐induced apoptosis and lipopolysaccharide‐stimulated expression of proinflammatory cytokines, which was reversed by inhibition of sphingosine‐1‐phosphate (S1P) signaling. Treatment of cardiomyocytes with CTRP1 also resulted in the increased production of cAMP, which was blocked by suppression of S1P signaling. The antiapoptotic and anti‐inflammatory actions of CTRP1 were cancelled by inhibition of adenylyl cyclase or knockdown of adiponectin receptor 1. Furthermore, blockade of S1P signaling reversed CTRP1‐mediated inhibition of myocardial infarct size, apoptosis, and inflammation after I/R in vivo. These data indicate that CTRP1 protects against myocardial ischemic injury by reducing apoptosis and inflammatory response through activation of the S1P/cAMP signaling pathways in cardiomyocytes, suggesting that CTRP1 plays a crucial role in the pathogenesis of ischemic heart disease.—Yuasa, D., Ohashi, K., Shibata, R., Mizutani, N., Kataoka, Y., Kambara, T., Uemura, Y., Matsuo, K., Kanemura, N., Hayakawa, S., Hiramatsu‐Ito, M., Ito, M., Ogawa, H., Murate, T., Murohara, T., Ouchi, N., C1q/TNF‐related protein‐1 functions to protect against acute ischemic injury in the heart. FASEB J. 30, 1065–1075 (2016). www.fasebj.org