Abstract
Iptakalim is a new ATP-sensitive potassium (K ATP) channel opener, and it inhibits the proliferation of pulmo-nary arterial smooth muscle cells (PASMCs) and pulmonary vascular remodeling. However, the underlying mech-anism remains unclear. In the present study, we found that iptakalim significantly decreased pulmonary artery pressure, inhibited pulmonary ariery remodeling and PKC-α overexpression in chronic hypoxia in a rat pulmonary hypertension model. Iptakalim reduced hypoxia-iduced expression of PKC-α, and abolished the effect of hypoxia on PASMC proliferation significantly in a dose-dependent manner in vitro. Moreover, these effects were abol-ished by glibenclamide, a selective K ATP channel antagonist. These results indicate that iptakalim inhibits PASMC proliferation and pulmonary vascular remodeling induced by hypoxia through downregulating the expression of PKC-α. Iptakalim can serve as a novel promising treatment for hypoxic pulmonary hypertension.
Highlights
Hypoxia-induced pulmonary hypertension is a common complication of residence at high altitudes and chronic lung diseases such as chronic obstructive pulmonary disease (COPD), various interstitial lung diseases, bronchiectasis, asthma, and sleep apnea[1,2]
0 Hypoxia Ipt(μmol/L) Gli(μmol/L) -. Our results from both in vivo and in vitro studies demonstrated that hypoxia increased the expression of protein kinase C (PKC)-α in pulmonary arterial smooth muscle cells (PASMCs) and promoted PASMC proliferation, which could be prevented by iptakalim
We found that iptakalim prevented hypoxia–induced pulmonary hypertension and vascular remodeling in rats, which may be due to suppressing the expression of PKC-α in PASMCs
Summary
Hypoxia-induced pulmonary hypertension is a common complication of residence at high altitudes and chronic lung diseases such as chronic obstructive pulmonary disease (COPD), various interstitial lung diseases, bronchiectasis, asthma, and sleep apnea[1,2]. Hypoxic pulmonary vascular structural remodeling is the key pathological basis of chronic hypoxic pulmonary hypertension[4,5], the underlying mechanism is not fully understood. Numerous studies have demonstrated that hypoxiainduced abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs) may be a key component of pulmonary vascular remodeling[6,7,8,9]. PKC-α is widely expressed and plays important roles in several cellular processes and pathologies, involving cancer, cardiovascular disorders, atherogenesis, thrombosis and pulmonary disease. Previous works suggested that PKC-α was closely associated with the abnormal proliferation of PASMCs and pulmonary vascular remodeling induced by cigarette smoking[13] or hypoxia[14,15]. The expression of PKC-α was significantly increased in the lung tissues from idiopathic pulmonary arterial hypertension patients[16]
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