Ramipril Protects the Endothelium from High Glucose–Induced Dysfunction through CaMKK<i>β</i>/AMPK and Heme Oxygenase-1 Activation

Tian, Shuo; Xia, Ge; Wu, Ke; Yang, Huabing; Liu, Yu

doi:10.1124/jpet.114.212928

Cited by 24 publications

(14 citation statements)

References 56 publications

(53 reference statements)

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“…Previous studies in similar models of T2DM as used in the current study demonstrated decreased vascular relaxation in the posterior ciliary artery (Davidson et al, 2012) and epineurial arterioles (Davidson et al, 2011), at week 12, and in the aorta at week 6–8 (Zhang et al, 2013; Tian et al, 2014; Latha et al, 2013). Several studies in animal models of vasculogenic ED reported endothelial dysfunction in the penile vascular bed occurring prior to this effect in the aorta, coronary, and mesenteric arteries, supporting our findings.…”

Section: Discussionsupporting

confidence: 64%

Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats

Musicki¹,

Hannan

Lagoda³

et al. 2016

Andrology

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Men with type 2 diabetes mellitus (T2DM) and erectile dysfunction (ED) have greater risk of cardiovascular events than T2DM men without ED, suggesting ED as a predictor of cardiovascular events in diabetic men. However, molecular mechanisms underlying endothelial dysfunction in the diabetic penis explaining these clinical observations are not known. We evaluated whether the temporal relationship between ED and endothelial dysfunction in the systemic vasculature in T2DM involves earlier redox imbalance and endothelial nitric oxidase synthase (eNOS) dysfunction in the penis than in the systemic vasculature, such as the carotid artery. Rats were rendered T2DM by high-fat diet for 2 weeks, followed by an injection with low-dose streptozotocin. After 3 weeks, erectile function (intracavernosal pressure) was measured and penes and carotid arteries were collected for molecular analyses of eNOS uncoupling, protein S-glutathionylation, oxidative stress (4-hydroxy-2-nonenal, 4-HNE), protein expression of NADPH oxidase subunit gp91phox, endothelium-dependent vasodilation in the carotid artery, and non-andrenergic, non-cholinergic (NANC) mediated cavernosal relaxation. Erectile response to electrical stimulation of the cavernous nerve and NANC mediated cavernosal relaxation were decreased (p<0.05), while relaxation of the carotid artery to acetylcholine was not impaired in T2DM rats. eNOS monomerization, protein expressions of 4-HNE and gp91phox, and protein S-glutathionylation, were increased (p<0.05) in the penis, but not in the carotid artery, of T2DM compared to nondiabetic rats. In conclusion, redox imbalance, increased oxidative stress by NADPH oxidase, and eNOS uncoupling, occur early in T2DM in the penis, but not in the carotid artery. These molecular changes contribute to T2DM ED, while vascular function in the systemic vasculature remains preserved.

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Section: Discussionsupporting

confidence: 64%

Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats

Musicki¹,

Hannan

Lagoda³

et al. 2016

Andrology

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“…,b); (iii) angiotensin‐converting enzyme (ACE1) inhibitors (Tian et al . ); (iv) antihypertensive therapy (Lüscher et al . , Kang et al .…”

Section: Nitric Oxidementioning

confidence: 99%

“…, Tian et al . ); (ix) reduced presence of apelin (Grisk , Zhong et al . ); (x) altered metabolism in the endothelial cells (De Zeeuw et al .…”

Section: Nitric Oxidementioning

confidence: 99%

Endothelial dysfunction and vascular disease - a 30th anniversary update

Vanhoutte¹,

et al. 2016

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The endothelium can evoke relaxations of the underlying vascular smooth muscle, by releasing vasodilator substances. The best-characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO) which activates soluble guanylyl cyclase in the vascular smooth muscle cells, with the production of cyclic guanosine monophosphate (cGMP) initiating relaxation. The endothelial cells also evoke hyperpolarization of the cell membrane of vascular smooth muscle (endothelium-dependent hyperpolarizations, EDH-mediated responses). As regards the latter, hydrogen peroxide (H O ) now appears to play a dominant role. Endothelium-dependent relaxations involve both pertussis toxin-sensitive G (e.g. responses to α -adrenergic agonists, serotonin, and thrombin) and pertussis toxin-insensitive G (e.g. adenosine diphosphate and bradykinin) coupling proteins. New stimulators (e.g. insulin, adiponectin) of the release of EDRFs have emerged. In recent years, evidence has also accumulated, confirming that the release of NO by the endothelial cell can chronically be upregulated (e.g. by oestrogens, exercise and dietary factors) and downregulated (e.g. oxidative stress, smoking, pollution and oxidized low-density lipoproteins) and that it is reduced with ageing and in the course of vascular disease (e.g. diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis toxin-sensitive pathway for NO release which favours vasospasm, thrombosis, penetration of macrophages, cellular growth and the inflammatory reaction leading to atherosclerosis. In addition to the release of NO (and EDH, in particular those due to H O ), endothelial cells also can evoke contraction of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors. Recent evidence confirms that most endothelium-dependent acute increases in contractile force are due to the formation of vasoconstrictor prostanoids (endoperoxides and prostacyclin) which activate TP receptors of the vascular smooth muscle cells and that prostacyclin plays a key role in such responses. Endothelium-dependent contractions are exacerbated when the production of nitric oxide is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes). They contribute to the blunting of endothelium-dependent vasodilatations in aged subjects and essential hypertensive and diabetic patients. In addition, recent data confirm that the release of endothelin-1 can contribute to endothelial dysfunction and that the peptide appears to be an important contributor to vascular dysfunction. Finally, it has become clear that nitric oxide itself, under certain conditions (e.g. hypoxia), can cause biased activation of soluble guanylyl cyclase leading to the production of cyclic inosine monophosphate (cIMP) rather than cGMP and hence causes contraction rather than relaxation of the underlying vascular smooth muscle.

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“…For instance, it is reported that mollugin has potential antioxidant and anti-inflammatory effects (21) that may involve in aortic endothelial protection against hyperglycemic environment. Similarly, it is reported that many agents such as, Propolise, Ramipril, and Hespiridin protect endothelium against damage induced by hyperglycemic environment through their antioxidant activities (22)(23)(24).…”

Section: Discussionmentioning

confidence: 99%

The Contractive Effect of Rubia tinctorum L. Extract on the Isolated Aorta Smooth Muscle and Its Protective Effect Against the Damage Caused by Hyperglycemic Solution in Rat

Nejat

Sedaghat

Vakili

et al. 2017

Jundishapur J Nat Pharm Prod

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Background: Few past studies have indicated antispasmodic and anti-oxidative effects of some species of Rubiaceae. Objectives: This study aimed to investigate the effect of hydroalcoholic extract of Rubia tinctorum L. (madder) root on the rat-isolated aorta and possible protective effects against the damage caused by hyperglycemic environment. Methods: The isolated thoracic aorta ring (with or without endothelium) was treated with phenylephrine (10 -6 M) or KCl (80 mM)

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Ramipril Protects the Endothelium from High Glucose–Induced Dysfunction through CaMKKβ/AMPK and Heme Oxygenase-1 Activation

Cited by 24 publications

References 56 publications

Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats

Mechanistic link between erectile dysfunction and systemic endothelial dysfunction in type 2 diabetic rats

Endothelial dysfunction and vascular disease - a 30th anniversary update

The Contractive Effect of Rubia tinctorum L. Extract on the Isolated Aorta Smooth Muscle and Its Protective Effect Against the Damage Caused by Hyperglycemic Solution in Rat

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