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Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the
M Sean McMurtry1, Sebastien Bonnet, Evangelos D Michelakis
1Vascular Biology Group, University of Alberta, Edmonton, Ontario, Canada.
Abstract:
Pulmonary arterial hypertension (PAH) is characterized by excessive pulmonary artery smooth muscle cell proliferation and impaired apoptosis leading to obstruction of resistance pulmonary arteries. We hypothesized that antiproliferative (rapamycin) and proapoptotic (statins) agents, already used clinically for other indications, would decrease experimental PAH, facilitating translation to human therapies. Prior studies in the rat monocrotaline-PAH model have indicated that simvastatin regresses and rapamycin prevents, but cannot reverse, PAH. Two PAH regression strategies (rapamycin monotherapy vs. rapamycin + atorvastatin) and one prevention strategy (simvastatin) were tested in a rat monocrotaline-PAH model. Adult male Sprague-Dawley rats were randomized to saline (n = 6) or monocrotaline (60 mg/kg ip, n = 36) treatment groups. Monocrotaline rats were randomized to gavage with vehicle, rapamycin (2.5 mgxkg(-1)xday(-1)), or rapamycin + atorvastatin (10 mgxkg(-1)xday(-1)) treatment groups, beginning 12 days post-monocrotaline. Echocardiographic and hemodynamic end points were assessed 2 wk later. Additional monocrotaline-PAH rats (n = 20) were randomized to vehicle or simvastatin (2 mgxkg(-1)xday(-1)) treatment groups and followed echocardiographically for 4 wk. Monocrotaline-PAH increased lung p70 S6 kinase phosphorylation, and this was reversed by rapamycin, confirming the biological activity of rapamycin. Despite the use of high doses, neither rapamcyin nor rapamycin + atorvastatin improved survival nor reduced PAH, vascular remodeling, and right ventricular hypertrophy. Although prophylactic simvastatin slowed PAH progression, by 4 wk PAH severity and mortality were not different from placebo. Apart from the new finding of p70 S6 kinase phosphorylation in monocrotaline-PAH, this is a negative therapeutic trial (none of these promising therapies improved monocrotaline-PAH). These negative results should be considered as human trials with these agents are underway (simvastatin) or proposed (rapamycin).
Insights
Rapamycin and statins, used for pulmonary arterial hypertension (PAH), did not improve survival or reduce disease severity in a rat model. These findings are crucial for ongoing human trials of these therapies.
Area of Science:
- Cardiovascular Research
- Pharmacology
Background:
- Pulmonary arterial hypertension (PAH) involves smooth muscle cell proliferation and apoptosis resistance.
- Existing clinical agents like rapamycin and statins were investigated for their therapeutic potential in PAH.
- Previous studies suggested rapamycin could prevent but not reverse PAH, while simvastatin showed regression potential.
Purpose of the Study:
- To evaluate the efficacy of rapamycin monotherapy and combination therapy with atorvastatin for PAH regression.
- To assess the preventative effect of simvastatin on the progression of experimental PAH.
- To determine if these agents could translate to effective human therapies for PAH.
Main Methods:
- The study utilized the rat monocrotaline-induced pulmonary arterial hypertension (PAH) model.
- Rats received treatments including rapamycin, rapamycin + atorvastatin, or simvastatin, with vehicle or saline controls.
- Echocardiography, hemodynamics, and histological assessments were performed to evaluate PAH severity and vascular remodeling.
Main Results:
- Rapamycin treatment reversed p70 S6 kinase phosphorylation, confirming its biological activity in the PAH model.
- Neither rapamycin nor rapamycin + atorvastatin improved survival or reduced PAH, vascular remodeling, or right ventricular hypertrophy.
- Prophylactic simvastatin slowed PAH progression but did not alter overall severity or mortality at 4 weeks compared to placebo.
Conclusions:
- High-dose rapamycin and atorvastatin failed to demonstrate therapeutic benefits in established experimental PAH.
- Simvastatin, used prophylactically, only slowed disease progression without preventing significant PAH development or mortality.
- These negative findings in a preclinical PAH model have significant implications for ongoing and proposed human clinical trials involving these agents.
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