Enhanced expression of transient receptor potential channels in idiopathic pulmonary arterial hypertension

Abstract

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.I diopathic pulmonary arterial hypertension (IPAH) is a fatal disease that causes right heart failure and death. The elevated pulmonary vascular resistance (PVR) and arterial pressure in IPAH patients result mainly from pulmonary vasoconstriction, vascular remodeling, and in situ thrombosis (1). A central aspect of pulmonary vascular remodeling is medial hypertrophy caused by sustained pulmonary vasoconstriction (2-4), excessive pulmonary artery smooth muscle cell (PASMC) proliferation (5), and inhibited PASMC apoptosis (6, 7), resulting in a narrowed vascular lumen and increased PVR. Although its etiology remains unclear, elevated levels of circulating mitogens, dysfunction or down-regulation of receptors and ion channels, upregulation of transporters, and heightened activity of elastases and glycoproteins have been implicated in IPAH (5,6,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Transient receptor potential (TRP) channel genes may encode subunits that form receptor-(ROC) and store-(SOC) operated Ca 2ϩ channels in many cell types, including PASMC and pulmonary artery endothelial cells (PAEC) (28,(30)(31)(32)(33)(34). Ca 2ϩ entry through ROC and SOC increases [Ca 2ϩ ] cyt , allowing for phosphorylation of signal transduction proteins and transcription factors (23,24,(35)(36)(37)(38), that are essential for the progression of the cell cycle (21). High levels of [Ca 2ϩ ] cyt and sufficient levels of Ca 2ϩ in the SR are required for vascular smooth muscle cell proliferation (22,25,39). Because they regulate SR and cytoplasmic Ca 2ϩ , CCE and SOC may play significant roles in regulating cell proliferation (28,29). This study tested the hypothesis that canonical TRP (TRPC...

Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange

“…At present it is not clear whether the very acute hypoxic vasoconstrictor response (occurring within seconds), the prolonged response (occurring within hours), and the initiation of the structural vascular remodeling process in chronic hypoxia are regulated by identical or different mechanisms (3). Recently, TRPC6 was found to be up-regulated in hypoxia-induced, as well as idiopathic chronic pulmonary hypertension (8,15). However, an indispensable role of TRPC6 in the development of hypoxiainduced chronic pulmonary hypertension can clearly be excluded by our study.…”

“…Although TRPC6 is expressed in many smooth-muscle tissues (11) and is thought to be an essential regulator of smooth-muscle contractility (12)(13)(14), direct evidence for a unique, nonredundant physiological role in the pulmonary circulation is still lacking. However, recently an up-regulation of TRPC6 has been shown in lung tissue from patients suffering from chronic pulmonary hypertension (15).…”

A common mechanism underlies stretch activation and receptor activation of TRPC6 channels

“…Our results reveal that TRPC6 channels are likely the direct sensors of mechanical stretch as well as DAG. Excessive smooth muscle proliferation in patients with idiopathic pulmonary arterial hypertension (IPAH) has been linked to elevated expression of TRPC6 (15), hence the disease may be mediated by increased mechanical sensitivity with higher TRPC6 expression. Recently, TRPC6 Ϫ/Ϫ mice were revealed to have elevated blood pressure, which was linked to a compensatory overexpression of TRPC3 channels.…”

“…TRPC6 channels mediate receptor-induced depolarization in smooth muscle cells (7,9), and opening of the related TRPC1 channel has been shown to be activated by stretch (14). In addition to being implicated in generating myogenic tone in arteries (6,9), elevated expression of TRPC6 channels has been linked to smooth muscle proliferation in patients with idiopathic pulmonary arterial hypertension (15). TRPC6 is also shown to be essential for proper function of podocytes that are exposed to hydrostatic pressure driving glomerular ultrafiltration in the kidney (13).…”

TRPC3: a versatile transducer molecule that serves integration and diversification of cellular signals

“…2c. Overexpression of TRPC3 as recently demonstrated for pathophysiological situations such as pulmonary arterial hypertension (Yu et al 2004) may cause membrane depolarization of vascular smooth muscle due to enhanced constitutive TRPC3 activity, leading to increased Ca 2+ entry through CaV1.2 (L-type) Ca 2+ channels.…”