Absence of the calcium-binding protein, S100A1, confers pulmonary hypertension in mice associated with endothelial dysfunction and apoptosis.
OBJECTIVE
S100A1, a 10-kDa, Ca(2+)-binding protein, is expressed in endothelial cells (ECs) and binds eNOS. Its absence is associated with impaired production of nitric oxide (NO) and mild systemic hypertension. As endothelial dysfunction contributes to clinical and experimental pulmonary hypertension (PH), we investigated the impact of deleting S100A1 in mice, on pulmonary haemodynamics, endothelial function, NO production, associated signalling pathways, and apoptosis.


RESULTS
Compared with wild-type (WT), S100A1-knock-out mice (KO) exhibited increased right ventricular (RV) weight/body weight ratio and elevated RV pressure in the absence of altered left ventricular filling pressures, accompanied by increase in wall thickness of muscularized pulmonary arteries and a reduction in microvascular perfusion. In isolated lung preparations, KO revealed reduced basal NO, blunted dose-responsiveness to acetylcholine, and augmented basal and angiotensin (AII)-induced pulmonary vascular resistance (R₀) compared with WT. Pre-treatment of KO lungs with S100A1 attenuated the AII-induced increase in pulmonary arterial pressure and R₀. S100A1-induced phosphorylation of eNOS, Akt, and ERK1/2 is attenuated in pulmonary EC of KO compared with WT. Basal and TNF-α-induced EC apoptosis is greater in KO vs. WT, and cell survival is enhanced by S100A1 treatment.


CONCLUSIONS
Our data demonstrate that the absence of S100A1 results in PH by disruption of its normal capacity to (i) enhance pulmonary EC function by induction of eNOS activity and NO levels via Akt/ERK1/2 pathways and (ii) promote EC survival. The ability of exogenously administered S100A1 to rescue this phenotype makes it an attractive therapeutic target in the treatment of PH.
Division of Cardiology, Department of Medicine.
Krystyna
K
Teichert-Kuliszewska
Division of Cardiology, Department of Medicine.
James N
JN
Tsoporis
Division of Cardiology, Department of Medicine.
Jean-Francois
JF
Desjardins
Department of Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Canada.
Jun
J
Yin
Department of Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Canada.
Liming
L
Wang
Department of Surgery, Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Toronto, Canada.
Wolfgang M
WM
Kuebler
Division of Cardiology, Department of Medicine parkertg@smh.ca.
Thomas G
TG
Parker
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D009418:S100 Proteins / Q000172:deficiency* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D066253:Vascular Remodeling
D018841:HSP90 Heat-Shock Proteins; D012333:RNA, Messenger; D009418:S100 Proteins; C110294:S100A1 protein; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
Apoptosis; Endothelium; Pulmonary hypertension; S100A1; eNOS