Inhibition of Notch3 prevents monocrotaline-induced pulmonary arterial hypertension

Abstract

It has been shown that activation of Notch3 signaling is involved in the development of pulmonary arterial hypertension (PAH) by stimulating pulmonary arteries remodeling, while the molecular mechanisms underlying this are still largely unknown. The aims of this study are to address these issues. Monocrotaline dramatically increased right ventricle systolic pressure to 39.0 ± 2.6 mmHg and right ventricle hypertrophy index to 53.4 ± 5.3% (P < 0.05 versus control) in rats, these were accompanied with significantly increased proliferation and reduced apoptosis of pulmonary vascular cells as well as pulmonary arteries remodeling. Treatment of PAH model with specific Notch inhibitor DAPT significantly reduced right ventricle systolic pressure to 26.6 ± 1.3 mmHg and right ventricle hypertrophy index to 33.5 ± 2.6% (P < 0.05 versus PAH), suppressed proliferation and enhanced apoptosis of pulmonary vascular cells as well as inhibited pulmonary arteries remodeling. Our results further indicated that level of Notch3 protein and NICD3 were increased in MCT-induced model of PAH, this was accompanied with elevation of Skp2 and Hes1 protein level and reduction of P27Kip1. Administration of rats with DAPT-prevented MCT induced these changes. Our results suggest that Notch3 signaling activation stimulated pulmonary vascular cells proliferation by Skp2-and Hes1-mediated P27Kip1 reduction, and Notch3 might be a new target to treat PAH.

TNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling

“…NOTCH2 is abundantly expressed in vascular SMCs and NOTCH2 deletion reduces SMC number and causes embryonic lethality4950. The reduction of NOTCH3 expression and HES1 signalling we observed was surprising given previous reports of NOTCH3 promoting PAH415152. However, these previous studies focussed on NOTCH3 and used DAPT as the therapeutic intervention in PAH models, which blocks NOTCH2 and NOTCH3 cleavage.…”

mTOR‐Notch3 signaling mediates pulmonary hypertension in hypoxia‐exposed neonatal rats independent of changes in autophagy

“…The Notch family proteins (Notch1‐4) are cell surface receptor proteins transducing signals between adjacent cells that are critical to cell fate determination. Notch3 is predominantly expressed in vascular smooth muscle, is involved in early pulmonary vascular development and is critical to the pulmonary vascular response to various injuries . In lungs of chronic hypoxia‐exposed neonatal rats and primary cultured PASMCs, we observed up‐regulated mTOR activity and Jagged‐1, NICD, and HES5 content.…”

Activation of AMPK Prevents Monocrotaline-Induced Extracellular Matrix Remodeling of Pulmonary Artery

“…Twenty-eight days after MCT injection, all surviving rats were anesthetized with an IP injection of 10% chloral hydrate (3 mL/kg). Hemodynamics were measured as described previously [ 18 ]. Briefly, right ventricle systolic pressure (RVSP) was measured using a Grass polygraph (Power Lab, Australia).…”