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

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Abstract
While Ca 2+ influx is essential for activation of the cell cycle machinery, the processes that regulate Ca 2+ influx in this context have not been fully elucidated. Electrophysiological and molecular studies have identified multiple Ca 2+ channel genes expressed in mammalian cells. Ca v 3.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 2+ channels in controlling cell proliferation conflict. The present study tested the hypothesis that T-type Ca 2+ channels, encoded by Ca v 3.x genes, control pulmonary artery smooth muscle cell proliferation and cell cycle progression. Using quantitative RT/PCR, immunocytochemistry, and immunohistochemistry we found that Ca v 3.1 was the predominant Ca v 3.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 Ca v 3.1 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 2+ channels are required for cell cycle progression and proliferation of human PA SMC.