Single-dose rosuvastatin ameliorates lung ischemia–reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension

Matsuo, Seiichiro; Saiki, Yuriko; Adachi, Osamu; Kawamoto, Shunsuke; Fukushige, Shinichi; Horii, Akira; Saiki, Yoshikatsu

doi:10.1016/j.jtcvs.2014.10.030

Cited by 18 publications

(20 citation statements)

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“…; Matsuo et al. ). As shown in Figure , the time‐dependent and similar increases in total and phosphorylated eNOS expressions suggest that most of the eNOS expression is in the active form in the established PAH.…”

Section: Discussionmentioning

confidence: 96%

“…3A). The levels of phosphorylated eNOS, a marker of increased eNOS activity (Matsuo et al 2015), were enhanced in the lungs at the 1-, 3-, 5-, and 8-week time points (Fig. 3B).…”

Section: Immunoblot Analysis Of Enos and Its Phosphorylation In Normamentioning

confidence: 93%

“…This anti‐phospho‐eNOS antibody was reported to detect endogenous levels of eNOS only when phosphorylated at Ser1177 (Matsuo et al. ). The optical density of each band was normalized to that of the corresponding β ‐actin band.…”

Section: Methodsmentioning

confidence: 99%

“…Equal amounts of total proteins (10 lg) were separated on 12.5% (w/v) polyacrylamide gels for sodium dodecyl sulfate polyacrylamide gel electrophoresis and transferred to a polyvinylidene difluoride membrane (0.2 lm pore size; Bio-Rad, Hercules, CA). The membranes were blocked with 5% (w/v) skim milk (for (1: 2000), which were diluted in immunoreaction enhancer solution (Can Get Signal; Toyobo, Osaka, Japan), followed by a 1-h incubation with secondary antibodies conjugated to horseradish peroxidase (1: 2000) (Matsuo et al 2015). The immune complexes were detected using an ECL select detection kit (GE Healthcare, Buckinghamshire, UK).…”

Section: Immunoblot Analysis Of the Expression Of Enos And Phospho-enosmentioning

confidence: 99%

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Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension

et al. 2017

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It is widely accepted that impaired bioavailability of endothelial nitric oxide (NO) plays a critical role in the pathophysiology of pulmonary arterial hypertension (PAH). However, there are published data that show that relatively many PAH patients respond favorably to acetylcholine‐induced pulmonary vasodilation during their follow‐up period, when diverse stages of the disorder are included. We hypothesized that NO bioavailability varies depending on the progression of PAH. Adult rats were exposed to the VEGF receptor blocker Sugen5416 and 3 weeks of hypoxia followed by return to normoxia for various additional weeks. All rats developed increased right ventricular systolic pressure (RVSP) and occlusive lesion formation at 1, 3, 5, and 8 weeks after the Sugen5416 injection. Acute NO synthase blockade did not change the elevated RVSP at the 1‐week time point, while it further increased RVSP markedly at the 3‐, 5‐, and 8‐week time points, leading to death in all rats tested at 8 weeks. Acetylcholine caused significant reduction in RVSP at the 8‐week but not the 1‐week time point, whereas sodium nitroprusside decreased the pressure similarly at both time points. Increased NO‐mediated cGMP production was found in lungs from the 8‐week but not the 1‐week time point. In conclusion, despite its initial impairment, NO bioavailability is restored and endogenous NO plays a critical protective role by counteracting severe pulmonary vasoconstriction in established stages of PAH in the Sugen5416/hypoxia/normoxia‐exposed rats. Our results provide solid pharmacological evidence for a major contribution of a NO‐suppressed vasoconstrictor component in the pathophysiology of established PAH.

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Section: Discussionmentioning

confidence: 96%

“…3A). The levels of phosphorylated eNOS, a marker of increased eNOS activity (Matsuo et al 2015), were enhanced in the lungs at the 1-, 3-, 5-, and 8-week time points (Fig. 3B).…”

Section: Immunoblot Analysis Of Enos and Its Phosphorylation In Normamentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

Section: Immunoblot Analysis Of the Expression Of Enos And Phospho-enosmentioning

confidence: 99%

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Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension

et al. 2017

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“…Macrophage infiltration into the wall of mesenteric resistance arteries is a common finding in DOCA-salt and ANG II-induced systemic hypertension (11,31,36). Macrophage infiltration into the wall of the pulmonary artery also occurs in animal models of pulmonary hypertension (45). Others (5,31,54) have found that macrophages infiltrate into the wall of the thoracic aorta in DOCA-salt, ANG II-infused, and stroke-prone spontaneously hypertensive rats, so the macrophage response may not be specific for MAs; however, macrophage infiltration into resistance arteries, other than MAs, has not been reported to our knowledge.…”

Section: Immune Activation In Hypertensionmentioning

confidence: 99%

Macrophage depletion lowers blood pressure and restores sympathetic nerve α₂-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats

Thang

Demel

Crawford

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Thang LV, Demel SL, Crawford R, Kaminski NE, Swain GM, Van Rooijen N, Galligan JJ. Macrophage depletion lowers blood pressure and restores sympathetic nerve ␣ 2-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol 309: H1186 -H1197, 2015. First published August 28, 2015; doi:10.1152/ajpheart.00283.2015.-We tested the hypothesis that vascular macrophage infiltration and O 2 Ϫ release impairs sympathetic nerve ␣ 2-adrenergic autoreceptor (␣2AR) function in mesenteric arteries (MAs) of DOCA-salt hypertensive rats. Male rats were uninephrectomized or sham operated (sham). DOCA pellets were implanted subcutaneously in uninephrectomized rats who were provided high-salt drinking water or high-salt water with apocynin. Sham rats received tap water. Blood pressure was measured using radiotelemetry. Treatment of sham and DOCA-salt rats with liposome-encapsulated clodronate was used to deplete macrophages. After 3-5, 10 -13, and 18 -21 days of DOCA-salt treatment, MAs and peritoneal fluid were harvested from euthanized rats. Norepinephrine (NE) release from periarterial sympathetic nerves was measured in vitro using amperometry with microelectrodes. Macrophage infiltration into MAs as well as TNF-␣ and p22 phox were measured using immunohistochemistry. Peritoneal macrophage activation was measured by flow cytometry. O 2 Ϫ was measured using dihydroethidium staining. Hypertension developed over 28 days, and apocynin reduced blood pressure on days 18 -21. O 2 Ϫ and macrophage infiltration were greater in DOCA-salt MAs compared with sham MAs after day 10. Peritoneal macrophage activation occurred after day 10 in DOCA-salt rats. Macrophages expressing TNF-␣ and p22 phox were localized near sympathetic nerves. Impaired ␣2AR function and increased NE release from sympathetic nerves occurred in MAs from DOCA-salt rats after day 18. Macrophage depletion reduced blood pressure and vascular O 2 Ϫ while restoring ␣2AR function in DOCA-salt rats. Macrophage infiltration into the vascular adventitia contributes to increased blood pressure in DOCA-salt rats by releasing O 2 Ϫ , which disrupts ␣2AR function, causing enhanced NE release from sympathetic nerves.salt-sensitive hypertension; immune activation; sympathetic nervous system; ␣2-adrenergic autoreceptors; amperometry NEW & NOTEWORTHYWe have identified a novel mechanism by which salt-sensitive hypertension disrupts normal function of the sympathetic nervous system. Antioxidants may be helpful in treating some forms of hypertension.INCREASED SYMPATHETIC nerve activity contributes to high blood pressure in some animal models of hypertension, including the DOCA-salt model (10, 57). Hypertension in the DOCA-salt model is driven by reduced renal mass (removal of one kidney), high circulating mineralocorticoid levels, and high salt intake (57). Elevated salt increases central sympathetic drive to the cardiovascular system (17, 48), but there are also alterations in the local mechanisms that modulate sympathetic neurotransmiss...

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Atorvastatin Protects Kidney from Remote Reperfusion Injury

Santos

Dourado

Silva

et al. 2018

Annals of Vascular Surgery

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Single-dose rosuvastatin ameliorates lung ischemia–reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension

Abstract: Single-dose rosuvastatin decreased IR injury in lungs affected by PH via 2 anti-inflammatory mechanisms: preserving eNOS function and inhibiting macrophage infiltration.

Cited by 18 publications

References 30 publications

Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension

Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension

Macrophage depletion lowers blood pressure and restores sympathetic nerve α₂-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats

Atorvastatin Protects Kidney from Remote Reperfusion Injury

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Single-dose rosuvastatin ameliorates lung ischemia–reperfusion injury via upregulation of endothelial nitric oxide synthase and inhibition of macrophage infiltration in rats with pulmonary hypertension

Abstract: Single-dose rosuvastatin decreased IR injury in lungs affected by PH via 2 anti-inflammatory mechanisms: preserving eNOS function and inhibiting macrophage infiltration.

Cited by 18 publications

References 30 publications

Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension

Inhibition of nitric oxide synthase unmasks vigorous vasoconstriction in established pulmonary arterial hypertension

Macrophage depletion lowers blood pressure and restores sympathetic nerve α2-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats

Atorvastatin Protects Kidney from Remote Reperfusion Injury

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Macrophage depletion lowers blood pressure and restores sympathetic nerve α₂-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats