Effects of chronic exposure to cigarette smoke on canonical transient receptor potential expression in rat pulmonary arterial smooth muscle

Abstract

Ran P, Lu W. Effects of chronic exposure to cigarette smoke on canonical transient receptor potential expression in rat pulmonary arterial smooth muscle. Am J Physiol Cell Physiol 306: C364 -C373, 2014. First published December 11, 2013 doi:10.1152/ajpcell.00048.2013To clarify the possible mechanism of cigarette smoke (CS)-induced pulmonary hypertension and furthermore provide effective targets for prevention and treatment, the effects of chronic CS on rat pulmonary arterial smooth muscle in vivo and nicotine treatment on rat pulmonary arterial smooth muscle cells (PASMCs) in vitro were investigated. In this study, we demonstrated that chronic CS exposure led to rat weight loss, right ventricular hypertrophy, and pulmonary arterial remodeling. A fluorescence microscope was used to measure intracellular calcium concentration ([Ca 2ϩ ]i) in rat distal PASMCs. Results showed that basal [Ca 2ϩ ]i and store-operated calcium entry (SOCE) levels in PASMCs from 3-and 6-mo CS-exposed rats were markedly higher than those in cells from the unexposed control animals (the increases in 6-mo CS group were more significant than that in 3-mo group), accompanied with increased canonical transient receptor potential 1 (TRPC1) and TRPC6 expression at both mRNA and protein levels in isolated distal PA. Simultaneously, in vitro study showed that nicotine treatment (10 nM) significantly increased basal [Ca 2ϩ ]i and SOCE and upregulated TRPC1 and TRPC6 expression in cultured rat distal PASMCs. TRPC siRNA knockdown strategies revealed that the elevations of basal [Ca 2ϩ ]i and SOCE induced by nicotine in PASMCs were TRPC1 and TRPC6 dependent. These results suggested that chronic CS-induced changes in vascular tone and structure in PA and the development of pulmonary hypertension might be largely due to upregulation of TRPC1 and TRPC6 expression in PASMCs, in which nicotine played an important role. cigarette smoke; pulmonary hypertension; TRPC; SOCE PULMONARY HYPERTENSION (PH) is characterized by a persistent and gradual increase of pulmonary arterial pressure, leading to right ventricular hypertrophy, and right ventricular failure, ultimately leading to death (1). PH is an important complication of chronic obstructive pulmonary disease (COPD) and also an independent risk factor that affects the course of COPD.Recent studies showed that up to 70% of patients with COPD suffer from at least mild PH (16). Cigarette smoke (CS) has been indicated as one of the main causes of COPD and PH; studies on smokers with mild COPD demonstrated that 25% of these patients had slow or progressive increase of pulmonary arterial pressure (7,21). Based on recent research findings, the traditional views of the pathogenesis of COPD patients with PH complications are questioned (2, 3). The traditional views believe that PH in COPD occurs as a consequence of alterations of the vasculature, such as vascular remodeling, associated with the emphysema and/or hypoxia. However, more and more evidence has shown that cigarette ingredients (such as nicotine) c...

Nicotine-Induced Airway Smooth Muscle Cell Proliferation Involves TRPC6-Dependent Calcium Influx Via α7 nAChR

“…However, more recent studies have indicated that TRPC6 is also an important component of SOCC and contributes to the SOCE process [12, 51, 52]. Evidences have also shown that upregulation of TRPC6 expression increases SOCC activity, which is related to elevated SOCE, and finally promotes the proliferation of PASMCs [53, 54]. However, the reasons behind these discrepancies remain unclear.…”

Ginsenoside Rb1 Attenuates Agonist-Induced Contractile Response via Inhibition of Store-Operated Calcium Entry in Pulmonary Arteries of Normal and Pulmonary Hypertensive Rats

“…Its circulating level is increased, its receptor density in PA is upregulated and vasoconstrictory effect is enhanced during PH; and antagonists of ET-receptors can effectively prevent and reverse PH [60,61,62,63,64,65,66]. Enhanced SOCE has been reported in many different models of experimental PH, including CHPH [34,67], monocrotaline-induced PH [36] and cigarette smoke-induced PH [68], and in patients of idiopathic pulmonary arterial hypertension (IPAH)[69,70,71]. It contributes to the elevated [Ca 2+ ] i of PASMCs, increased pulmonary vascular tone, enhanced vasoreactivity and vascular remodeling, and plays a crucial pathogenic role in PH [28,34,54,72].…”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Interestingly, nicotine itself activates both TRPA1 ) and TRPV1, albeit at much higher concentrations at which it activates nicotinic acetylcholine receptors (Kichko et al, 2013). Parenthetically, nicotine also appears to activate TRPC1 and TRPC6 channels (Wang et al, 2014a). The implications of this finding to smoking-associated lung diseases will be discussed later.…”

“…Taken together, these results imply that both TRPC1 and TRPC6 are important players in the pathogenesis of pulmonary hypertension. Indeed, chronic cigarette smoke exposure upregulates TRPC1 and TRPC6 in mice; in these animals, the normal vascular tone is restored only when both TRPC1 and TRPC6 are knocked down by siRNA (Wang et al, 2014a).…”