Vascular endothelial dysfunction in Duchenne muscular dystrophy is restored by bradykinin through upregulation of eNOS and nNOS

Dabiré, Hubert; Barthélémy, I.; Blanchard‐Gutton, Nicolas; Sambin, Lucien; Sampedrano, Carolina Carlos; Gouni, Vassiliki; Unterfinger, Yves; Aguilar, Pablo; Thibaud, Jean-Laurent; Ghaleh, Bijan; Bizé, Alain; Pouchelon, Jean‐Louis; Blot, Stéphane; Berdeaux, Alain; Hittinger, Luc; Chetboul, Valérie; Su, Jin Bo

doi:10.1007/s00395-011-0240-6

Cited by 45 publications

(35 citation statements)

References 42 publications

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“…As this is a global knockout, it is difficult to delineate the mechanism(s) responsible for this adverse cardiac response to exercise training. For example, the contribution of NO produced via NOS1 in the skeletal muscle cannot be overlooked, as demonstrated in other disease models [7]. In fact, mice deficient in NOS1 have increased skeletal muscle fatigue due to an immediate decrease in vasodilation after brief, mild exercise even though the strength of the muscle was sustained [30].…”

Section: Discussionmentioning

confidence: 99%

Neuronal nitric oxide synthase is indispensable for the cardiac adaptive effects of exercise

et al. 2013

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Rationale Exercise results in beneficial adaptations of the heart that can be directly observed at the ventricular myocyte level. However, the molecular mechanism(s) responsible for these adaptations are not well understood. Interestingly, signaling via neuronal nitric oxide synthase (NOS1) within myocytes results in similar effects as exercise. Objective Thus, the objective was to define the role NOS1 plays in the exercise-induced beneficial contractile effects in myocytes. Methods and Results After an 8 week aerobic interval training program, exercise-trained (Ex) mice had higher VO2max and cardiac hypertrophy compared to sedentary (Sed) mice. Ventricular myocytes from Ex mice had increased NOS1 expression and nitric oxide production compared to myocytes from Sed mice. Remarkably, acute NOS1 inhibition normalized the enhanced contraction (shortening and Ca2+ transients) in Ex myocytes to Sed levels. The NOS1 effect on contraction was mediated via greater Ca2+cycling that resulted from increased phospholamban phosphorylation. Intriguingly, a similar aerobic interval training program on NOS1 knockout mice failed to produce any beneficial cardiac adaptations (VO2max, hypertrophy, and contraction). Conclusions These data demonstrate that the beneficial cardiac adaptations observed after exercise training were mediated via enhanced NOS1 signaling. Therefore, it is likely that beneficial effects of exercise may be mimicked by the interventions that increase NOS1 signaling. This pathway may provide a potential novel therapeutic target in cardiac patients who are unable or unwilling to exercise.

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Section: Discussionmentioning

confidence: 99%

Neuronal nitric oxide synthase is indispensable for the cardiac adaptive effects of exercise

et al. 2013

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“…Endothelial dysfunction has long been recognized as an initiating event in the development of numerous cardiovascular diseases [14, 30]. This recognition is due to its influence on the consequential reduction in the synthesis and/or release of eNOS-mediated NO [29, 31], as well as damage to the EDHF dilator pathway [17, 25]. In short, improvement of endothelial dysfunction may be a novel treatment option for cardiovascular diseases in the future.…”

Section: Discussionmentioning

confidence: 99%

Crocin Improves the Endothelial Function Regulated by Kca3.1 Through ERK and Akt Signaling Pathways

Yang

Liu

et al. 2018

Cell Physiol Biochem

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Background/Aims: Based on the protective effect of crocin against cardiovascular diseases, we hypothesize that crocin could improve endothelial function through activating the eNOS(endothelial nitric oxide synthase) /NO pathway and/or the intermediate-conductance Ca²⁺-activated K⁺ channels (KCa3.1). Methods: In this study, rat aortic rings were used to assess the regulatory effect of crocin on vascular tone and nitric oxide, prostacyclin, and KCa3.1, all endothelial vasodilators, were analyzed for effects by crocin. The expression profiles of p-eNOS, total-eNOS, p-ERK, total-ERK, p-Akt, total-Akt, KCa3.1, CD31, thrombomodulin, ICAM-1 and VCAM-1 were tested by western blotting. KCa3.1 was also analyzed by qPCR and immunofluorescence staining. Fluorescence and confocal microscopy were used to determine NO generation and intracellular Ca²⁺. Both EdU and MTT assays were used to evaluate cell viability. Cellular migration was assessed using transwell assay. Results: Crocin relaxed pre-contracted artery rings through either NO or KCa3.1, but not PGI, in an endothelium-dependent manner. Furthermore, crocin increased p-eNOS, total-eNOS expression and NO production as well as intracellular Ca²⁺ in both HUVECs and HUAECs (Human Umbilical Artery Endothelial cells). Crocin also stimulated the expression of CD31, thrombomodulin and vascular cell adhesion molecule 1 (VCAM-1), as well as increased cellular proliferation and migration in vitro. Interestingly, we determined for the first time that by blocking or silencing KCa3.1 there was inhibition of crocin induced upregulation of p-eNOS and total-eNOS. Correspondingly, the KCa3.1 inhibitor TRAM-34 also reduced the expression of CD31, thrombomodulin and VCAM-1, as well as diminished intracellular Ca²⁺, cellular proliferation and migration. Finally, crocin stimulated the expression of p-ERK, total-ERK, p-Akt and total-Akt, however suppression of MEK and Akt inhibited this expression profile in endothelial cells. Conclusion: In the present study, these data strongly support the hypothesis that crocin could improve endothelial function through stimulation of the eNOS/NO pathway and other endothelial markers. This functional improvement is regulated by KCa3.1 via the MEK/ERK and PI3K/Akt signaling pathway.

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“…Aorta rings were mounted in isolated vessels chambers, as previously described (18). They were randomly submitted to a sham procedure without any cardiac arrest or to 15 min of untreated ventricular fibrillation as previously described.…”

Section: In Vitro Analysis Of Vascular Functionmentioning

confidence: 99%

Comparative Effect of Hypothermia and Adrenaline During Cardiopulmonary Resuscitation in Rabbits

Kohlhauer¹,

Darbera²,

Lidouren³

et al. 2014

Shock

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Vascular endothelial dysfunction in Duchenne muscular dystrophy is restored by bradykinin through upregulation of eNOS and nNOS

Cited by 45 publications

References 42 publications

Neuronal nitric oxide synthase is indispensable for the cardiac adaptive effects of exercise

Neuronal nitric oxide synthase is indispensable for the cardiac adaptive effects of exercise

Crocin Improves the Endothelial Function Regulated by Kca3.1 Through ERK and Akt Signaling Pathways

Comparative Effect of Hypothermia and Adrenaline During Cardiopulmonary Resuscitation in Rabbits

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