Protective role of the antidiabetic drug metformin against chronic experimental pulmonary hypertension.
OBJECTIVE
Pulmonary arterial hypertension (PAH) is associated with increased contraction and proliferation of pulmonary vascular smooth muscle cells. The anti-diabetic drug metformin has been shown to have relaxant and anti-proliferation properties. We thus examined the effect of metformin in PAH.


METHODS
Metformin effects were analysed in hypoxia- and monocrotaline-induced PAH in rats. Ex vivo and in vitro analyses were performed in lungs, pulmonary artery rings and cells.


RESULTS
In hypoxia- and monocrotaline-induced PAH, the changes in mean pulmonary arterial pressure and right heart hypertrophy were nearly normalized by metformin treatment (100 mg.kg(-1).day(-1)). Pulmonary arterial remodelling occurring in both experimental models of PAH was also inhibited by metformin treatment. In rats with monocrotaline-induced PAH, treatment with metformin significantly increased survival. Metformin increased endothelial nitric oxide synthase phosphorylation and decreased Rho kinase activity in pulmonary artery from rats with PAH. These effects are associated with an improvement of carbachol-induced relaxation and reduction of phenylephrine-induced contraction of pulmonary artery. In addition, metformin inhibited mitogen-activated protein kinase activation and strongly reduced pulmonary arterial cell proliferation during PAH. In vitro, metformin directly inhibited pulmonary artery smooth muscle cell growth.


CONCLUSIONS
Metformin protected against PAH, regardless of the initiating stimulus. This protective effect may be related to its anti-remodelling property involving improvement of endothelial function, vasodilatory and anti-proliferative actions. As metformin is currently prescribed to treat diabetic patients, assessment of its use as a therapy against PAH in humans should be easier.
Agard
C
C
INSERM, U915, Nantes, France.
Rolli-Derkinderen
M
M
Dumas-de-La-Roque
E
E
Rio
M
M
Sagan
C
C
Savineau
J P
JP
Loirand
G
G
Pacaud
P
P
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004789:Enzyme Activation; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D008687:Metformin / Q000494:pharmacology* / Q000627:therapeutic use; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D054460:rho-Associated Kinases / Q000378:metabolism
D007004:Hypoglycemic Agents; D008687:Metformin; D052250:Nitric Oxide Synthase Type III; D054460:rho-Associated Kinases; D020928:Mitogen-Activated Protein Kinases