Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension.
Pulmonary vascular medial hypertrophy caused by excessive pulmonary artery smooth muscle cell (PASMC) proliferation is a major cause for the elevated pulmonary vascular resistance in patients with idiopathic pulmonary arterial hypertension (IPAH). Increased Ca(2+) influx is an important stimulus for PASMC proliferation. Transient receptor potential (TRP) channel genes encode Ca(2+) channels that are responsible for Ca(2+) entry during cell proliferation. Normal human PASMC expressed multiple canonical TRP (TRPC) isoforms; TRPC6 was highly expressed and TRPC3 was minimally expressed. The protein expression of TRPC6 in normal PASMC closely correlated with the expression of Ki67, suggesting that TRPC6 expression is involved in the transition of PASMC from quiescent phase to mitosis. In lung tissues and PASMC from IPAH patients, the mRNA and protein expression of TRPC3 and -6 were much higher than in those from normotensive or secondary pulmonary hypertension patients. Inhibition of TRPC6 expression with TRPC6 small interfering RNA markedly attenuated IPAH-PASMC proliferation. These results demonstrate that expression of TRPC channels correlates with the progression of the cell cycle in PASMC. TRPC channel overexpression may be partially responsible for the increased PASMC proliferation and pulmonary vascular medial hypertrophy in IPAH patients.
Yu
Ying
Y
Department of Medicine, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
Fantozzi
Ivana
I
Remillard
Carmelle V
CV
Landsberg
Judd W
JW
Kunichika
Naomi
N
Platoshyn
Oleksandr
O
Tigno
Donna D
DD
Thistlethwaite
Patricia A
PA
Rubin
Lewis J
LJ
Yuan
Jason X-J
JX
D000328:Adult; D000368:Aged; D001794:Blood Pressure; D015220:Calcium Channels / Q000235:genetics; D002453:Cell Cycle; D002455:Cell Division; D004261:DNA Replication; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007473:Ion Channels / Q000235:genetics*; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D008938:Mitosis; D011651:Pulmonary Artery / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; D014655:Vascular Resistance / Q000502:physiology
D015220:Calcium Channels; D007473:Ion Channels; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; C489571:TRPC4 ion channel; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human