Statin therapy in pulmonary hypertension

Background: The mevalonate pathway generates endogenous cholesterol and intermediates including geranylgeranyl pyrophosphate (GGPP). By reducing GGPP production, statins exert pleiotropic or cholesterol-independent effects. The potential regulation of GGPP homeostasis through dietary intake and the interaction with concomitant statin therapy is unknown. Methods: We developed a sensitive HPLC technique to quantify dietary GGPP and conducted proteomics, qRT-PCR screening and western blot to determine signaling cascades, gene expression, protein-protein interaction and protein membrane trafficking in wild type and transgenic rats. Results: GGPP contents were highly variable depending on food source that differentially regulated blood GGPP levels in rats. Diets containing intermediate and high GGPP reduced or abolished the effects of statins in rats with hypoxia- and monocrotaline-induced pulmonary hypertension: this was rescuable by methyl-allylthiosulfinate and methyl-allylthiosulfinate-rich garlic extracts. In human pulmonary artery smooth muscle cells (HPASMCs) treated with statins, hypoxia activated RhoA in an extracellular GGPP-dependent manner. Hypoxia-induced ROCK2/Rab10 signaling was prevented by statin and recovered by exogenous GGPP. The hypoxia-activated RhoA/ROCK2 pathway in rat and HPASMCs upregulated the expression of Ca 2+ -sensing receptor (CaSR) and hypoxia-induced mitogenic factor/FIZZ1 (HIMF), a mechanism attenuated by statin treatment and regained with exogenous GGPP. Rab10-knockdown almost abrogated hypoxia-promoted CaSR membrane-trafficking, a process diminished by statin and resumed by exogenous GGPP. Hypoxia-induced pulmonary hypertension was reduced in rats with CaSR mutated at the binding motif of HIMF and the interaction between dietary GGPP and statin efficiency was abolished. In humans fed with a high GGPP diet, blood GGPP levels were increased, and this abolished statin-lowering effects on plasma GGPP and hypoxia-enhanced RhoA activity of blood monocytes that were both also rescued by garlic extracts. Conclusions: There is important dietary regulation of GGPP levels that interferes with the effects of statin therapy in experimental pulmonary hypertension. These observations rely on a key and central role of i) RhoA-ROCK2 cascade activation and ii) Rab10-faciliated CaSR membrane trafficking with iii) subsequent overexpression and binding of HIMF to CaSR. These findings warrant clinical investigation for the treatment of pulmonary hypertension and perhaps other diseases by combining statin together with garlic-derived methyl-allylthiosulfinate or garlic extracts and thus circumventing dietary GGPP variations.

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Clinical benefit of pulmonary hypertension using statin therapy: a population-based cohort study

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.wcp2018.0_po4-5-17 ◽

2018 ◽

Vol WCP2018 (0) ◽

pp. PO4-5-17

Author(s):

CHUNG-YU CHEN

Keyword(s):

Pulmonary Hypertension ◽

Cohort Study ◽

Statin Therapy ◽

Clinical Benefit ◽

Population Based

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Abstract 263: Evaluation of Survival Benefit of Statins in Patients with Pulmonary Hypertension and Chronic Obstructive Pulmonary Disease: A Propensity Score Matching Study

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.263 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Luise Holzhauser ◽

Ninel Hovnanian ◽

Parham Eshtehardi ◽

Khalid Mojadidi ◽

David Goodman-Meza ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Hypertension ◽

Propensity Score ◽

Statin Therapy ◽

Propensity Score Matching ◽

Survival Benefit ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Statin Group ◽

All Cause Mortality

Background: Pulmonary hypertension (PH) is a multifactorial disease characterized by endothelial dysfunction and inflammation. In line with this, pleiotropic effects of statins have been found beneficial in PH resulting in hemodynamic improvement. However, the role of statins in subgroups of PH, especially inflammation triggered chronic obstructive pulmonary disease (COPD) is unknown and their effect on mortality has not yet been studied. Methods: Consecutive patients ≥18 years with severe PH (pulmonary artery systolic pressure ≥60 mmHg) and preserved left ventricular function (ejection fraction ≥50%) defined by transthoracic echocardiograms were included from January 2002 to August 2012. Patients were divided into two groups based on being on statin therapy for 12 consecutive months after diagnosis of PH. Propensity score matching was performed for all baseline demographics, comorbidities, labs, lipid profile, and medications with ratio matching of 1 (treated) to 5 (untreated controls). Subgroup analysis was done based on COPD status. Study endpoint was 1-year all-cause mortality. Results: 2,363 patients (age 71±16; 31% male) were included, 140 (6%) patients were on statin therapy. 1-year mortality for the entire population was 34%. Following propensity score matching, 137 patients on statin (statin group) and 625 patients not on statin (controls), all-cause mortality was significantly lower in statin group compared to controls (15.3% vs. 36.2%, HR 0.38 [95% CI 0.25, 0.60], p<0.001). After stratifying patients based on COPD status, while statins significantly reduced 1-year all-cause mortality in patients without COPD (HR 0.30 [95%CI 0.16, 0.56], p<0.001), patients with COPD did not show a survival benefit from statins (HR 0.54 [95%CI 0.28, 1.05], p=0.069). Conclusions: In this study, we identify statin therapy as an independent predictor of lower 1-year mortality in patients with severe PH but interestingly not in the subgroup of patients with COPD. This observation might be linked to the high severity of PH in our study population and less likely to the lack of anti-inflammatory effects. However the overall survival benefit in patients with severe PH is a novel and promising finding that needs to be confirmed in large randomized trials.

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