Abstract
Injury/dysfunction of the endothelium of pulmonary arteries contributes to hypoxia-induced pulmonary hypertension (HPH). We investigated whether C1q/tumor necrosis factor-related protein-9 (CTRP9), a newly identified cardiovascular agent, has protective roles in the development of HPH. HPH was induced in adult male rats by chronic hypobaric hypoxia. CTRP9 overexpression by adeno-associated virus (AAV)-CTRP9 transfection attenuated the increases in right ventricular systolic pressure, right ventricular hypertrophy index, and pulmonary arterial remodeling of rats under hypoxia. Importantly, CTRP9 overexpression improved endothelium-dependent vasodilation in pulmonary arterioles in HPH rats. CTRP9 overexpression enhanced expression of phosphorylated 5′-adenosine monophosphate-activated protein kinase (p-AMPK) and phosphorylated endothelial nitric oxide synthase (p-eNOS), and reduced phosphorylated extracellular signal-regulated protein kinase (p-ERK1/2) expression in pulmonary microvascular endothelial cells (PMVECs) of HPH rats. In cultured PMVECs, CTRP9 not only preserved the decrease of AMPK and eNOS phosphorylation level and nitric oxide (NO) production induced by hypoxia, but also blocked the increase in hypoxia-induced ERK1/2 phosphorylation level and endothelin (ET)-1 production. Furthermore, the effects of CTRP9 were interrupted by inhibitors or knockdown of AMPK. CTRP9 enhances NO production and reduces ET-1 production by regulating AMPK activation. CTRP9 could be a target for HPH.
Highlights
Injury/dysfunction of the endothelium of pulmonary arteries contributes to hypoxia-induced pulmonary hypertension (HPH)
These results suggested a correlation between a reduced C1q/tumor necrosis factor-related protein-9 (CTRP9) concentration in serum and HPH development
In contrast with group H + CTRP9, pretreatment with compound C before hypoxia and CTRP9 treatment inhibited the effect of CTRP9 on -adenosine monophosphate-activated protein kinase (p-AMPK)/phosphorylated endothelial nitric oxide synthase (p-endothelial nitric oxide synthase (eNOS))/nitric oxide (NO) and p-ERK1/2/ET-1 signaling pathways in pulmonary microvascular endothelial cells (PMVECs). These results suggested that CTRP9 regulated production of the vasoactive substances NO and ET-1 through AMPK-mediated phosphorylation of eNOS and ERK1/2 in PMVECs
Summary
Injury/dysfunction of the endothelium of pulmonary arteries contributes to hypoxia-induced pulmonary hypertension (HPH). CTRP9 overexpression by adenoassociated virus (AAV)-CTRP9 transfection attenuated the increases in right ventricular systolic pressure, right ventricular hypertrophy index, and pulmonary arterial remodeling of rats under hypoxia. CTRP9 overexpression improved endothelium-dependent vasodilation in pulmonary arterioles in HPH rats. CTRP9 overexpression enhanced expression of phosphorylated 5′-adenosine monophosphate-activated protein kinase (p-AMPK) and phosphorylated endothelial nitric oxide synthase (p-eNOS), and reduced phosphorylated extracellular signal-regulated protein kinase (p-ERK1/2) expression in pulmonary microvascular endothelial cells (PMVECs) of HPH rats. The “pulmonary vascular endothelium” refers to the innermost layer of a blood vessel along the route of the heart and lungs It is crucial for the homeostasis of the pulmonary c irculation[3]. New approaches for HPH treatment should attempt to amend such endothelial dysfunction
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