The effects of atorvastatin on pulmonary arterial hypertension and expression of p38, p27, and Jab1 in rats

Inflammation is an increasingly recognized hallmark of pulmonary hypertension (PH). Statins have been shown to attenuate key pathologic mechanisms via pleiotropic effects in animal models. However, clinical benefit of statins in patients with PH is unknown and their effect on mortality has not been studied. We performed a retrospective analysis of patients between January 2002 to January 2012, with severe PH (pulmonary artery systolic pressure ≥60 mmHg) and preserved left ventricular function (ejection fraction ≥50%), defined by transthoracic echocardiograms. Patients were divided into two groups based on statin therapy for 12 consecutive months after diagnosis of PH. Propensity score matching was performed. Subgroup analysis was done based on COPD status. Study endpoint was 1-year all-cause mortality and hospitalization. 2363 patients (age 71 ± 16; 31% male) were included; 140 (6%) were on statin therapy. Overall 1-year mortality was 34%. Following propensity score matching, 138 patients were included in the statin group and 624 patients in the no-statin group; all-cause mortality was significantly lower in the statin group compared with the no-statin group [15.2 vs. 33.8%, HR 0.42 (95% CI 0.27, 0.66), p < 0.001], but hospitalization was comparable between two groups. After stratifying patients based on COPD status, patients with COPD showed a marginally significant survival benefit from statins [HR 0.53 (95% CI 0.26, 1.10), p = 0.09]; and statins significantly reduced 1-year all-cause mortality in patients without COPD [HR 0.36 (95% CI 0.19, 0.67), p = 0.001]. We found no significant difference in the effect of statins on patients with COPD compared to those without (p = 0.16). Statin therapy is associated with reduced mortality risk in patients with severe PH and preserved left ventricular function. This beneficial effect was not found to be dependent on COPD status. These novel findings should be confirmed in large randomized trials.

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Statin therapy improves survival in patients with severe pulmonary hypertension: a propensity score matching study

Holzhauser

Hovnanians

Eshtehardi

et al. 2017

Heart Vessels

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Are statins beneficial for the treatment of pulmonary hypertension?

Wang

Yang

Wang

2017

Chronic Diseases and Translational Medicine

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Pulmonary hypertension (PH) is a condition characterized by vasoconstriction and vascular remodeling with a poor prognosis. The current medical treatments available are supportive care therapy and pulmonary vascular-targeted therapy. Targeted treatments for PH include prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors; however, these treatments cannot reverse pulmonary vascular remodeling. Recently, many novel treatment options involving drugs such as statins have been emerging. In this review, we attempt to summarize the current knowledge of the role of statins in PH treatment and their potential clinical effects. Many basic researches have proved that statins can be helpful for the treatment of PH both in vitro and in experimental models. The main mechanisms underlying the effects of statins are restoration of endothelial function, attenuation of pulmonary vascular remodeling, regulation of gene expression, regulation of intracellular signaling processes involved in PH, anti-inflammatory responses, and synergy with other targeted drugs. Nevertheless, clinical researches, especially randomized controlled trials for PH are rare. The current clinical researches show contrasting results on the clinical effects of statins in patients with PH. Carefully designed randomized, controlled trials are needed to test the safety and efficacy of statins for PH treatment.

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Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension

Barnes,

Ito,

Che

et al. 2023

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pulmonary arterial hypertension (PAH) is a disease characterized by increased vasoconstriction and vascular remodeling. Pulmonary artery smooth muscle cells (PASMC) highly express the transcription factor hypoxia inducible factor-1α (HIF-1α), yet the role of PASMC HIF-1α in the development of PAH remains controversial. To study the role of SMC HIF-1α in the pulmonary vascular response to acute and chronic hypoxia, we employed a gain of function strategy to stabilize HIF-1α in PASMC by generating mice lacking prolyl hydroxylase domain (PHD) 1 and 2 in SM22α-expressing cells. This strategy increased HIF-1α expression and transcriptional activity under conditions of normoxia and hypoxia. Acute hypoxia increased right ventricular systolic pressure (RVSP) in control, but not in SM22α-PHD1/2-/- mice. Chronic hypoxia increased RVSP and vascular remodeling more in control SM22α-PHD1/2+/+ than in SM22α-PHD1/2-/- mice. In vitro studies demonstrated increased contractility and myosin light chain phosphorylation in isolated PHD1/2+/+ compared to PHD1/2-/- PASMC under both normoxic and hypoxic conditions. After chronic hypoxia there was more p27 and less vascular remodeling in SM22α-PHD1/2-/- compared to SM22α-PHD1/2+/+ mice. Hypoxia increased p27 in PASMC isolated from control patients, but not in cells from patients with idiopathic PAH (IPAH). These findings highlight a SM22α-expressing cell specific role for HIF-1α in the inhibition of pulmonary vasoconstriction and vascular remodeling. Modulating HIF-1α expression in PASMC may represent a promising preventative and therapeutic strategy for patients with PAH.

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The effects of atorvastatin on pulmonary arterial hypertension and expression of p38, p27, and Jab1 in rats

Cited by 5 publications

References 23 publications

Statin therapy improves survival in patients with severe pulmonary hypertension: a propensity score matching study

Statin therapy improves survival in patients with severe pulmonary hypertension: a propensity score matching study

Are statins beneficial for the treatment of pulmonary hypertension?

Loss of prolyl hydroxylase 1 and 2 in SM22α-expressing cells prevents Hypoxia-Induced pulmonary hypertension

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