Statins ameliorate pulmonary hypertension secondary to left ventricular dysfunction through the Rho‐kinase pathway and NADPH oxidase

Chen, I‐Chen; Tan, Mian‐Shin; Wu, Bin–Nan; Chai, Chee‐Yin; Yeh, Jwu‐Lai; Chou, Shah‐Hwa; Chen, Ing‐Jun; Dai, Zen‐Kong

doi:10.1002/ppul.23610

Cited by 16 publications

(17 citation statements)

References 45 publications

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“…The SIM doses used in this study are commonly used in rodent studies, as SIM has a low bioavailability of 5% after oral administration compared with other routes, such as intraperitoneal and inhalatory . The pharmacokinetics and metabolic factors related to rodents could explain the fact that oral SIM doses used in experimental studies usually are higher compared with the therapeutic dose used in humans (0.5‐1.0 mg/kg/d) …”

Section: Methodsmentioning

confidence: 99%

Acute simvastatin treatment restores cerebral functional capillary density and attenuates angiotensin II‐induced microcirculatory changes in a model of primary hypertension

et al. 2017

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Section: Methodsmentioning

confidence: 99%

Acute simvastatin treatment restores cerebral functional capillary density and attenuates angiotensin II‐induced microcirculatory changes in a model of primary hypertension

et al. 2017

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“…In this regard, ROS has widely been recognized as an inducer of vascular wall cell proliferation and vasoconstriction [ 18 ]. Therefore, targeting mitochondria-derived ROS production may offer particularly effective in preventing hypoxia-induced PH [ 9 , 55 , 56 ]. Indeed, an inhibition of NOX/vascular peroxidase 1 (VPO1) pathway and inflammatory reaction showed a possibility to prevent cardiovascular remodeling in the hypoxia-induced pulmonary hypertensive rat model [ 57 ].…”

Section: Discussionmentioning

confidence: 99%

NOX4 expression and distal arteriolar remodeling correlate with pulmonary hypertension in COPD

et al. 2018

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BackgroundPulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is suggested as the consequence of emphysematous destruction of vascular bed and hypoxia of pulmonary microenvironment, mechanisms underpinning its pathogenesis however remain elusive. The dysregulated expression of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases and superoxide generation by pulmonary vasculatures have significant implications in the hypoxia-induced PH.MethodsIn this study, the involvement of NADPH oxidase subunit 4 (NOX4) in pulmonary arteriolar remodeling of PH in COPD was investigated by ascertaining the morphological alteration of pulmonary arteries and pulmonary blood flow using cardiac magnetic resonance imaging (cMRI), and the expression and correlation of NOX4 with pulmonary vascular remodeling and pulmonary functions in COPD lungs.ResultsResults demonstrated that an augmented expression of NOX4 was correlated with the increased volume of pulmonary vascular wall in COPD lung. While the volume of distal pulmonary arteries was inversely correlated with pulmonary functions, despite it was positively associated with the main pulmonary artery distensibility, right ventricular myocardial mass end-systolic and right ventricular myocardial mass end-diastolic in COPD. In addition, an increased malondialdehyde and a decreased superoxide dismutase were observed in sera of COPD patients. Mechanistically, the abundance of NOX4 and production of reactive oxygen species (ROS) in pulmonary artery smooth muscle cells could be dynamically induced by transforming growth factor-beta (TGF-β), which in turn led pulmonary arteriolar remodeling in COPD lungs.ConclusionThese results suggest that the NOX4-derived ROS production may play a key role in the development of PH in COPD by promoting distal pulmonary vascular remodeling.

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“…All protocols were approved by the Animal Research Committee of Kaohsiung Medical University. A Wistar rat PH model (6 weeks old; weight, 220 g) was created by ascending aortic banding, as described previously [20,21]. Briefly, left parasternal thoracotomy in the fourth intercostal space was performed in rats anesthetized with sodium pentobarbitone (20 mg/kg, i.p.)…”

Section: Rat Model Of Group II Phmentioning

confidence: 99%

The beneficial effects of angiotensin-converting enzyme II (ACE2) activator in pulmonary hypertension secondary to left ventricular dysfunction

Chen¹,

Lin²,

Liu³

et al. 2020

Int. J. Med. Sci.

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Pulmonary hypertension (PH) is a lethal and rapidly progressing disorder if left untreated, but there is still no definitive therapy. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism underlying PH. Among the vasomediators of the pulmonary circulation is the renin-angiotensin system (RAS), the involvement of which in the development of PH has been proposed. Within the RAS, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), is an important regulator of blood pressure, and has been implicated in cardiovascular disease and PH. In this study, we investigated the effects of the ACE2 activator diminazene aceturate (DIZE) on the development of PH secondary to left ventricular dysfunction. A model of PH secondary to left ventricular dysfunction was established in 6-week-old Wistar rats by ascending aortic banding for 42 days. The hemodynamics and pulmonary expression of ACE, Ang II, ACE2, Ang-(1-7), and the Ang-(1-7) MAS receptor were investigated in the early treatment group, which was administered DIZE (15 mg/kg/day) from days 1 to 42, and in the late treatment group, administered DIZE (15 mg/kg/day) from days 29 to 42. Sham-operated rats served as controls. DIZE ameliorated mean pulmonary artery pressure, pulmonary arteriolar remodeling, and plasma brain natriuretic peptide levels, in addition to reversing the overexpression of ACE and up-regulation of both Ang-(1-7) and MAS, in the early and late treatment groups. DIZE has therapeutic potential for preventing the development of PH secondary to left ventricular dysfunction through ACEII activation and the positive feedback of ANG-(1-7) on the MAS receptor. A translational study in humans is needed to substantiate these findings.

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Statins ameliorate pulmonary hypertension secondary to left ventricular dysfunction through the Rho‐kinase pathway and NADPH oxidase

Cited by 16 publications

References 45 publications

Acute simvastatin treatment restores cerebral functional capillary density and attenuates angiotensin II‐induced microcirculatory changes in a model of primary hypertension

Acute simvastatin treatment restores cerebral functional capillary density and attenuates angiotensin II‐induced microcirculatory changes in a model of primary hypertension

NOX4 expression and distal arteriolar remodeling correlate with pulmonary hypertension in COPD

The beneficial effects of angiotensin-converting enzyme II (ACE2) activator in pulmonary hypertension secondary to left ventricular dysfunction

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