Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension.
Alterations of the nitric oxide receptor, soluble guanylate cyclase (sGC) may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). In the present study, the expression of sGC in explanted lung tissue of PAH patients was studied and the effects of the sGC stimulator BAY 63-2521 on enzyme activity, and haemodynamics and vascular remodelling were investigated in two independent animal models of PAH. Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was demonstrated by immunohistochemistry. Upregulation of sGC was detected, similarly to humans, in the structurally remodelled smooth muscle layer in chronic hypoxic mouse lungs and lungs from monocrotaline (MCT)-injected rats. BAY 63-2521 is a novel, orally available compound that directly stimulates sGC and sensitises it to its physiological stimulator, nitric oxide. Chronic treatment of hypoxic mice and MCT-injected rats, with fully established PAH, with BAY 63-2521 (10 mg x kg(-1) x day(-1)) partially reversed the PAH, the right heart hypertrophy and the structural remodelling of the lung vasculature. Upregulation of soluble guanylate cyclase in pulmonary arterial smooth muscle cells was noted in human idiopathic pulmonary arterial hypertension lungs and lungs from animal models of pulmonary arterial hypertension. Stimulation of soluble guanylate cyclase reversed right heart hypertrophy and structural lung vascular remodelling. Soluble guanylate cyclase may thus offer a new target for therapeutic intervention in pulmonary arterial hypertension.
Schermuly
R T
RT
University of Giessen Lung Centre, Giessen, Germany. ralph.schermuly@uglc.de
Stasch
J-P
JP
Pullamsetti
S S
SS
Middendorff
R
R
Müller
D
D
Schlüter
K-D
KD
Dingendorf
A
A
Hackemack
S
S
Kolosionek
E
E
Kaulen
C
C
Dumitrascu
R
R
Weissmann
N
N
Mittendorf
J
J
Klepetko
W
W
Seeger
W
W
Ghofrani
H A
HA
Grimminger
F
F
D000818:Animals; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006162:Guanylate Cyclase / Q000096:biosynthesis* / Q000502:physiology*; D006439:Hemodynamics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000201:enzymology*; D006984:Hypertrophy; D000860:Hypoxia; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D016686:Monocrotaline / Q000494:pharmacology; D011651:Pulmonary Artery / Q000201:enzymology*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase
D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D016686:Monocrotaline; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase