Mechanisms for Enhanced Endothelium-Derived Hyperpolarizing Factor-Mediated Responses in Microvessels in Mice

Ohashi, Junko; Sawada, A.; Nakajima, Shuro; Noda, Kazuki; Takaki, Akira; Shimokawa, Hiroaki

doi:10.1253/circj.cj-12-0197

Cited by 43 publications

(45 citation statements)

References 42 publications

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“…We have previously demonstrated that the eNOS system has diverse vasodilator functions for NO-generating system in large arteries and EDHF/H 2 O 2 -generating system in microvessels (Takaki et al 2008;Ohashi et al 2012). Cardiovascular risk factors, such as diabetes mellitus, hypertension and hyperlipidemia impair endothelial function and suppress eNOS activity, thus promoting atherosclerosis and cardiovascular diseases (Shimokawa 1999;Vanhoutte 2009).…”

Section: Beneficial Effects Of Olm Plus Azl On Endothelial Functionmentioning

confidence: 99%

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

Noda

Hosoya

Nakajima

et al. 2012

Tohoku J. Exp. Med.

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Many studies have aimed to identify anti-atherogenic agents in cardiovascular medicine. We have recently demonstrated that the combination therapy with olmesartan (OLM), an angiotensin II receptor blocker, and azelnidipine (AZL), a dihydroprydine calcium-channel blocker, improves endothelial function in diabetic Apolipoprotein-deficient (ApoE −/− ) mice. In the present study, we examined whether this combination therapy also inhibits atherosclerosis in mice. We used male control and streptozocin-induced diabetic ApoE −/− mice. Diabetic ApoE −/− mice were orally treated for 5 weeks with vehicle (Untreated), OLM (30 mg/ kg/day), AZL (10 mg/kg/day), their combination (OLM+AZL), or hydralazine (HYD, 5 mg/kg/day) as an antihypertensive control. At 5 weeks, systolic blood pressure was significantly elevated in Untreated but was normalized in OLM+AZL and HYD. The atherosclerosis area in the thoracic aorta, perivascular fibrosis and medial thickness of the coronary arteries were increased in Untreated and were ameliorated in OLM+AZL but not in HYD. Staining with a fluorescent probe dihydroethidium showed that production of reactive oxygen species was increased in Untreated, and ameliorated in OLM+AZL. Consistent with these findings, macrophage infiltration in the kidney and the expression of receptor for advanced glycation end-products in the heart, kidney and liver were increased in Untreated and were all ameliorated in OLM+AZL, associated with up-regulation of endothelial NO syntheses (eNOS). In conclusion, the combination therapy with OLM and AZL exerts anti-atherogenic effect in diabetic ApoE −/− mice through suppression of oxidative stress and activation of eNOS, independent of its blood pressure-lowering effects. Clinically, this combination therapy may be useful for patients with hypertension, hyperlipidemia and diabetes.

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Section: Beneficial Effects Of Olm Plus Azl On Endothelial Functionmentioning

confidence: 99%

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

Noda

Hosoya

Nakajima

et al. 2012

Tohoku J. Exp. Med.

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“…7 Although the molecular mechanism of the vasorelaxing activity of the EDHF has not been completely understood, it is thought that the mechanism is achieved via the occurence of the hyperpolarization as a result of the opening of the K + channels. 7 EDHF is defined as the endothelium-mediated relaxation response, which is observed after the PGI 2 -NO block is made. 7 …”

Section: Endothelium-derived Hyperpolarizing Factormentioning

confidence: 99%

“…7 EDHF is defined as the endothelium-mediated relaxation response, which is observed after the PGI 2 -NO block is made. 7 …”

Section: Endothelium-derived Hyperpolarizing Factormentioning

confidence: 99%

Contribution of Rho-kinase and Adenosine Monophosphate-Activated Protein Kinase Signaling Pathways to Endothelium-Derived Contracting Factors Responses

Balcilar

Özakça

Altan

2017

tjps

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Vascular tonus is controlled by endothelium-derived relaxing factor (EDRF), endothelium-derived hyperpolarizing factor (EDHF) and endotheliumderived contracting factor (EDCF) under physiological circumstances. In pathological conditions, impairment of endothelium-derived relaxation can be caused by both decrease in EDRF release and increase in EDCF release. The increase in EDCF is observed with diseases such as hypertension and diabetes. The contribution of Rho-kinase and activated protein kinase (AMPK), which have opposite effects, to the increased EDCF responses was investigated. Rho-kinases are the effectors of Rho which is one of the small guanosine triphosphate-binding proteins. They increase cytosolic Ca +2 concentration and cause vascular smooth muscle to contract, keeping myosin light chain (MLC) in phosphorylated state by affecting myosin phosphatase target subunit which dephosphorylates the MLC. The activities of Rho-kinases increase with the increase of EDCF function. AMPK is the energy sensor of the cell. It provides a vasculoprotective effect by causing endothelium-dependent and endothelium-independent relaxation in smooth muscle. In contrast to Rho-kinase pathway activity, AMPK pathway activity decreases with diseases in which the EDCF function increases. In cases such as diabetes and hypertension that endothelial function impairs toward vasocontraction, it is considered that evaluating Rho-kinase and AMPK pathways which mediate contraction and relaxation in vascular smooth muscle respectively, would provide clues on choosing therapeutic target for pathologies in which endothelial dysfunction is observed. ÖZFizyolojik koşullarda vasküler tonus endotel kaynaklı rahatlatıcı faktörü (EDRF), endotel kaynaklı hiperpolarizasyon faktörü (EDHF) ve endotel kaynaklı kasılma faktörü (EDCF) tarafından kontrol edilmektedir. Patolojik durumlarda endotel kaynaklı gevşemenin azalması, EDRF üretimindeki azalmaya bağlı olabileceği gibi EDCF düzeyinin artmasına da bağlı olabilmektedir. EDCF hipertansiyon, diyabet gibi hastalıklarda artmaktadır. Diyabet, hipertansiyon gibi patolojik koşullarda artan EDCF yanıtına birbirine ters etki yapan Rho-kinaz ve aktive protein kinaz (AMPK) yolaklarının katkısı olabileceği düşünülmektedir. Rho-kinazlar küçük guanozin trifosfat-bağlı proteinlerden biri olan Rho'nun efektörüdür. Rho-kinazlar hafif zincir miyozini (MLC) defosforile eden miyozin fosfataz hedef altbirimine etki ederek MLC'nin fosforile halde kalmasının sağlayarak sitozolik Ca +2 konsantrasyonu artırır ve vasküler düz kasın kasılmasına neden olurlar. Rho-kinazların aktivitesi EDCF yanıtlarının arttığı hipertansiyon, kalp yetmezliği ve diyabet gibi hastalıklarda artmaktadır. AMPK ise hücrenin enerji sensörü olarak düşünülmektedir. Vasküler düz kasta endotel bağımlı ve bağımsız gevşemeyi sağlayarak vasküloprotektif etki sağlamaktadır. AMPK'nin aktivitesi Rho-kinaz yolağının aktivitesinin tersine EDCF fonksiyonunun arttığı hipertansiyon ve diyabet gibi hastalıklarda azalmaktadır. Endotel fonksiyonunun vazokonstriksiyon y...

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“…The mechanisms of enhanced EDHF-mediated vasodilatation have been well illustrated. 29 The regulation of endothelium function varies according to the site and the type of blood vessel. 30 The contribution of each individual EDRF to endothelium-dependent relaxation differs between the aorta and the small vessels; for example, NO plays a prominent role in aorta, but EDHF is prominent in the mesenteric artery.…”

Section: Involvement Of Intracellular Camp Formation In the Inhibitormentioning

confidence: 99%

Linoleic Acid Attenuates Endothelium-Derived Relaxing Factor Production by Suppressing cAMP-Hydrolyzing Phosphodiesterase Activity

Wei

Takeuchi

Watanabe

2013

Circ J

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Mechanisms for Enhanced Endothelium-Derived Hyperpolarizing Factor-Mediated Responses in Microvessels in Mice

Cited by 43 publications

References 42 publications

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

Anti-Atherogenic Effects of the Combination Therapy with Olmesartan and Azelnidipine in Diabetic Apolipoprotein E-Deficient Mice

Contribution of Rho-kinase and Adenosine Monophosphate-Activated Protein Kinase Signaling Pathways to Endothelium-Derived Contracting Factors Responses

Linoleic Acid Attenuates Endothelium-Derived Relaxing Factor Production by Suppressing cAMP-Hydrolyzing Phosphodiesterase Activity

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