RATIONALE: Pulmonary hypertension (PH) is a life-threatening disease, characterized by pulmonary vascular remodeling. Abnormal smooth muscle cell proliferation is a primary hallmark of chronic hypoxia-induced PH. Essential for cell growth are alterations in the intracellular Ca(2+) homeostasis. Classical transient receptor potential (TRPC) proteins have been suggested to contribute to PH development, as TRPC1 and TRPC6 are predominantly expressed in precapillary pulmonary arterial smooth muscle cells (PASMC). Studies in a TRPC6-deficient mouse model revealed an essential function of TRPC6 in acute but not in chronic hypoxia. OBJECTIVES: We aimed to identify the importance of TRPC1 in the pathogenesis of chronic hypoxia-induced PH in mice. METHODS: TRPC1 expression analysis was performed using real-time polymerase chain reaction. TRPC1 function was assessed by in vivo experiments in TRPC1(-/-) animals as well as in isolated precapillary murine PASMC after TRPC1 knockdown by TRPC1-specific small interfering RNAs. MEASUREMENTS AND MAIN RESULTS: Only TRPC1 mRNA was up-regulated under hypoxia in isolated murine PASMC (1% O2 for 72 h). Hypoxia-induced proliferation of murine PASMC was attenuated in cells treated with small interfering RNA against TRPC1 and in cells isolated from TRPC1(-/-) animals compared with untreated and wild-type cells. TRPC1(-/-) mice did not develop PH in response to chronic hypoxia (FI(O2) 0.10 for 21 d) and had less vascular muscularization but a similar degree of right ventricular hypertrophy compared with wild-type mice. CONCLUSIONS: Our results indicate an important role of TRPC1 in pulmonary vascular remodeling underlying the development of hypoxia-induced PH.
RATIONALE: Pulmonary hypertension (PH) is a life-threatening disease, characterized by pulmonary vascular remodeling. Abnormal smooth muscle cell proliferation is a primary hallmark of chronic hypoxia-induced PH. Essential for cell growth are alterations in the intracellular Ca(2+) homeostasis. Classical transient receptor potential (TRPC) proteins have been suggested to contribute to PH development, as TRPC1 and TRPC6 are predominantly expressed in precapillary pulmonary arterial smooth muscle cells (PASMC). Studies in a TRPC6-deficient mouse model revealed an essential function of TRPC6 in acute but not in chronic hypoxia. OBJECTIVES: We aimed to identify the importance of TRPC1 in the pathogenesis of chronic hypoxia-induced PH in mice. METHODS:TRPC1 expression analysis was performed using real-time polymerase chain reaction. TRPC1 function was assessed by in vivo experiments in TRPC1(-/-) animals as well as in isolated precapillary murinePASMC after TRPC1 knockdown by TRPC1-specific small interfering RNAs. MEASUREMENTS AND MAIN RESULTS: Only TRPC1 mRNA was up-regulated under hypoxia in isolated murinePASMC (1% O2 for 72 h). Hypoxia-induced proliferation of murinePASMC was attenuated in cells treated with small interfering RNA against TRPC1 and in cells isolated from TRPC1(-/-) animals compared with untreated and wild-type cells. TRPC1(-/-) mice did not develop PH in response to chronic hypoxia (FI(O2) 0.10 for 21 d) and had less vascular muscularization but a similar degree of right ventricular hypertrophy compared with wild-type mice. CONCLUSIONS: Our results indicate an important role of TRPC1 in pulmonary vascular remodeling underlying the development of hypoxia-induced PH.
Authors: Christopher J Rhodes; Pablo Otero-Núñez; John Wharton; Emilia M Swietlik; Sokratis Kariotis; Lars Harbaum; Mark J Dunning; Jason M Elinoff; Niamh Errington; A A Roger Thompson; James Iremonger; J Gerry Coghlan; Paul A Corris; Luke S Howard; David G Kiely; Colin Church; Joanna Pepke-Zaba; Mark Toshner; Stephen J Wort; Ankit A Desai; Marc Humbert; William C Nichols; Laura Southgate; David-Alexandre Trégouët; Richard C Trembath; Inga Prokopenko; Stefan Gräf; Nicholas W Morrell; Dennis Wang; Allan Lawrie; Martin R Wilkins Journal: Am J Respir Crit Care Med Date: 2020-08-15 Impact factor: 21.405