EXPRESS: TMEM16A/ANO1 Inhibitor T16Ainh-A01 Reversed Monocrotaline-induced Rat Pulmonary Arterial Hypertension

Experimental proof that TMEM16A was involved in the development of the monocrotaline (MCT) -induced pulmonary arterial hypertension (PAH) model through ERK1/2 activation, and it is a potential target for PAH treatment. A PAH rat model was established by intraperitoneal administration of monocrotaline (MCT). Noninvasive pulsed-wave Doppler and histological analysis was performed , and it revealed proliferation and remodeling of pulmonary arterioles and right ventricle hypertrophy. In addition, TMEM16A, PCNA-a proliferate marker, P-ERK1/2 increased following MCT treatment. Expression of TMEM16A in the pulmonary arteries was co-localized with a specific marker of vascular smooth muscle α-SMA. Then, a specific inhibitor of TMEM16A-T16Ainh-A01 was administered to PAH rats. It was found to alleviate the remodeling of pulmonary arterioles and right ventricle hypertrophy significantly, and decrease the upregulation of PCNA in MCT-induced pulmonary arteries. In addition, T16Ainh-A01 could inhibit the activation of ERK1/2 in PAH model. TMEM16A mediated the proliferation and remodeling of pulmonary arterioles in the MCT-induced PAH model. ERK1/2 pathway is one of downstream factors. Long-term use of T16Ainh-A01 in vivo could alleviate remodeling and pressure in PAH.