Function and role of voltage-gated sodium channel Na_V1.7 expressed in aortic smooth muscle cells

Abstract

Na ϩ channel currents (INa) are expressed in several types of smooth muscle cells. The purpose of this study was to evaluate the expression of INa, its functional role, pathophysiology in cultured human (hASMCs) and rabbit aortic smooth muscle cells (rASMCs), and its association with vascular intimal hyperplasia. In whole cell voltage clamp, I Na was observed at potential positive to Ϫ40 mV, was blocked by tetrodotoxin (TTX), and replacing extracellular Na ϩ with N-methyl-D-glucamine in cultured hASMCs. In contrast to native aorta, cultured hASMCs strongly expressed SCN9A encoding NaV1.7, as determined by quantitative RT-PCR. I Na was abolished by the treatment with SCN9A small-interfering (si)RNA (P Ͻ 0.01). TTX and SCN9A siRNA significantly inhibited cell migration (P Ͻ 0.01, respectively) and horseradish peroxidase uptake (P Ͻ 0.01, respectively). TTX also significantly reduced the secretion of matrix metalloproteinase-2 6 and 12 h after the treatment (P Ͻ 0.01 and P Ͻ 0.05, respectively). However, neither TTX nor siRNA had any effect on cell proliferation. L-type Ca 2ϩ channel current was recorded, and INa was not observed in freshly isolated rASMCs, whereas TTX-sensitive I Na was recorded in cultured rASMCs. Quantitative RT-PCR and immunostaining for NaV1.7 revealed the prominent expression of SCN9A in cultured rASMCs and aorta 48 h after balloon injury but not in native aorta. In conclusion, these studies show that INa is expressed in cultured and diseased conditions but not in normal aorta. The NaV1.7 plays an important role in cell migration, endocytosis, and secretion. NaV1.7 is also expressed in aorta after balloon injury, suggesting a potential role for NaV1.7 in the progression of intimal hyperplasia. vascular smooth muscle; sodium channel; SCN9A; balloon injury VOLTAGE-GATED NA ϩ CHANNELS (I Na ) are generally involved in the generation and propagation of action potentials in nerve fiber (5), skeletal muscle, and cardiac muscle (13). At present, 10 ␣-subunit (SCN1-6, 8-11A) and 4 ␤-subunit (SCN␤ 1-4 ) genes have been identified with isoform expression dependent on cell types (24). I Na has also been identified in cultured smooth muscle cells such as coronary arterial (3), pulmonary arterial (25), and bronchial (17) smooth muscle cells. However, the pathophysiology and function of I Na and its molecular characteristics are not fully understood in cultured human aortic smooth muscle cells (hASMCs).Vascular smooth muscle cells undergo cellular proliferation and migration in the formation of atherosclerosis and intimal hyperplasia (6,30). Smooth muscle cells in atherosclerotic plaques or neointimal hyperplasia are different from native contractile smooth muscle cells, but rather resemble cultured vascular smooth muscle cells (36). Since I Na is expressed only in the cultured and proliferative state, but not in the freshly isolated aortic smooth muscle cells (7), it is likely that this phenotypical change contributes to the cell proliferation, migration, and endocytosis, which mirrors exocytosis (33) in ...

Voltage-Gated Sodium Channel Nav1.7 Maintains the Membrane Potential and Regulates the Activation and Chemokine-Induced Migration of a Monocyte-Derived Dendritic Cell Subset

“…These, in combination with the similar number of IKCa1 channels in the IDC subpopulations, support our conclusion that Nav1.7 channel is an active regulator of the membrane potential in CD1a + IDC. As it was shown earlier, the existence of a negative membrane potential in various immune cells is necessary for the proper activation of Ca 2+ -dependent signaling (44). We propose that the presence and activity of IKCa1 channels in both IDC subtypes may be responsible for maintaining the negative membrane potential necessary for a sustained Ca 2+ signaling during differentiation.…”

The cardiac sodium current Nav1.5 is functionally expressed in rabbit bronchial smooth muscle cells

“…Most commonly, the Na V 1.7 subtype has been found, especially in vascular tissue, but its functional role remains unclear (18,21,29). Several studies have pointed to the greater tendency for Na ϩ currents to be expressed in cultured than freshly dispersed cells, leading to suggestions that they participate in cell proliferation or migration (9,27).…”

“…In phasic tissues, such as uterine, lymphatic, vas deferens, portal vein, and gastrointestinal smooth muscle, they may play a part in the generation and/or propagation of spontaneous electrical activity underlying myogenic contractions (14,15,29,31,38). However, they have also been found in a variety of tonic arterial smooth muscles (7,9,21,27), although mostly only in cultured cells, suggesting that they are indicative of an altered phenotype (9,27). However, this idea has been challenged by the finding that Na ϩ currents were found in freshly dispersed mesenteric artery cells, so long as precautions, such as avoidance of the use of papain, are taken with the dispersal method (3).…”

Vinpocetine Suppresses Pathological Vascular Remodeling by Inhibiting Vascular Smooth Muscle Cell Proliferation and Migration

“…Moreover, vinpocetine is a potent voltage-gated sodium channel blocker (Bönöczk et al, 2000). The voltage-gated sodium channel has been found in several types of SMCs, and these channels seem to be important for SMC migration but not proliferation (Platoshyn et al, 2005;Meguro et al, 2009). Besides SMCs, the anti-inflammatory effects of vinpocetine on vascular cells and macrophages (Jeon et al, 2010b) may contribute to the inhibitory effects of vinpocetine in neointima formation.…”