Kinase

NF-κB

Cell biology

Biology

Apoptosis

Autophagy

Signal transduction

Cancer research

Biochemistry

Protein kinase A

AMPK

Internal medicine

Pulmonary hypertension

Pharmacology

Medicine

Chemistry

Right ventricular hypertrophy

AMP-activated protein kinase

Ventricle

Life Sciences

It has been shown that activation of autophagy is involved in the development of pulmonary arterial hypertension (PAH). Meanwhile, activation of nuclear factor-kappaB (NF-κB) has been found to induce autophagy in several types of human diseases including cancer and cardiac diseases. However, it is still unknown whether NF-κB mediates autophagy activation in PAH, and whether activation of adenosine monophosphate-activated protein kinase (AMPK) benefits PAH by modulation of NF-κB and autophagy.Rat models of PAH were established by intraperitoneally injection of monocrotaline (MCT). The right ventricle systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and percentage of medial wall thickness (%MT) were performed to evaluate the development of PAH. The translocation of NF-κB p65 from cytosol to nucleus, the protein levels of LC3A, LC3B, and RND3 were determined by immunoblotting. Metformin was used to activate AMPK.NF-κB and autophagy were significantly activated in MCT-induced PAH rats, this was accompanied with the reduction of RND3. Pharmacological inhibition of NF-κB suppressed MCT-induced activation of autophagy and down-regulation of RND3 expression and reduced RVSP, RVHI, and %MT in MCT-induced PAH rats. In addition, activation of AMPK by metformin suppressed NF-κB-mediated autophagy activation and down-regulation of RND3 and therefore reduced RVSP, RVHI, and %MT in MCT-induced PAH.NF-κB-induced autophagy activation and consequent down-regulation of RND3 contributes to the development of PAH in MCT-treated rats. Activation of AMPK prevents the development of PAH by targeting on NF-κB to suppress autophagy and vascular remodeling.

Activation of AMPK prevents monocrotaline-induced pulmonary arterial hypertension by suppression of NF-κB-mediated autophagy activation