Low-Voltage-Activated (T-Type) Calcium Channels Control Proliferation of Human Pulmonary Artery Myocytes

• Published in: Circulation research 2005-04, Vol.96 (8), p.864-872
• Main Authors: Rodman, David M, Reese, Katherine, Harral, Julie, Fouty, Brian, Wu, Songwei, West, James, Hoedt-Miller, Marloes, Tada, Yuji, Li, Kai-Xun, Cool, Carlyne, Fagan, Karen, Cribbs, Leanne
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; Calcium Channels, T-Type - analysis; Calcium Channels, T-Type - genetics; Calcium Channels, T-Type - physiology; Cell Proliferation; Cells, Cultured; Diltiazem - pharmacology; Fundamental and applied biological sciences. Psychology; Humans; Lung - metabolism; Mibefradil - pharmacology; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - metabolism; Myocytes, Smooth Muscle - cytology; Myocytes, Smooth Muscle - metabolism; Pulmonary Artery - cytology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering - pharmacology; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000163066.07472.ff

While Ca influx is essential for activation of the cell cycle machinery, the processes that regulate Ca influx in this context have not been fully elucidated. Electrophysiological and molecular studies have identified multiple Ca channel genes expressed in mammalian cells. Cav3.x gene family members, encoding low voltage-activated (LVA) or T-type channels, were first identified in the central nervous system and subsequently in non-neuronal tissue. Reports of a potential role for T-type Ca channels in controlling cell proliferation conflict. The present study tested the hypothesis that T-type Ca channels, encoded by Cav3.x genes, control pulmonary artery smooth muscle cell proliferation and cell cycle progression. Using quantitative RT/PCR, immunocytochemistry, and immunohistochemistry we found that Cav3.1 was the predominant Cav3.x channel expressed in early passage human pulmonary artery smooth muscle cells in vitro and in the media of human pulmonary arteries, in vivo. Selective blockade of Cav3.1 expression with small interfering RNA (siRNA) and pharmacological blockade of T-type channels completely inhibited proliferation in response to 5% serum and prevented cell cycle entry. These studies establish that T-type voltage-operated Ca channels are required for cell cycle progression and proliferation of human PA SMC.