The team of Professor Kong Wei of Peking University Medical College of Circ Res reveals the work of PHB2 in smooth muscle energy metabolism and phenotypic regulation.

Vascular smooth muscle cells have strong phenotypic plasticity, and under the action of pathological stimulation such as growth factors, inflammatory factors or mechanical stretching, smooth muscle cells will undergo transformation
from contractile phenotype to secretion phenotype, inflammatory phenotype, etc.
A number of reports have shown that the phenotypic transformation of smooth muscle cells is an early step and key link
in the pathogenesis of various vascular diseases such as atherosclerosis, restenosis after vascular injury, aneurysm, and vascular calcification.
Recent studies suggest that phenotypic transformation of smooth muscle cells is accompanied by a metabolic transition
from oxidative phosphorylation to aerobic glycolysis.
However, the causal relationship between smooth muscle cell metabolic reprogramming and phenotypic transformation, and the key molecules involved in regulation, are currently unclear
.
Finding potential endogenous molecules and mechanisms that maintain the phenotype of vascular smooth muscle contraction by regulating smooth muscle cell metabolism is of great significance
for maintaining vascular homeostasis and preventing cardiovascular disease.

On October 6, 2022, Professor Kong Wei's research group of the Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University Medical College, published a research paper entitled "PHB2 Maintains the Contractile Phenotype of VSMCs by Counteracting PKM2 Splicing" online at Circulation Research.
The role and molecular mechanism of PHB2 in regulating the metabolism of vascular smooth muscle cells, maintaining the contractile phenotype of smooth muscle cells, and inhibiting the formation of new endomesis after vascular injury were revealed, providing a new target for the treatment of related diseases
.

The researchers found that compared with the control mice, the expression of smooth muscle contractor proteins was reduced, the proliferation level of smooth muscle cells increased, and the formation of new endometris increased was increased
compared with the control mice after carotid artery conduction strain.
Suggests that smooth muscle cell PHB2 can inhibit the formation
of neonatal endometrium after vascular injury.
Using proteomics and immunoprecipitation, the researchers found that PHB2 can bind to the RGG-box domain of hnRNPA1 through its C-terminus
.
Next, using adenoviruses that overexpressed the RGG-box domain of hnRNPA1, the researchers found that blocking the binding of PHB2-hnRNPA1 can promote the phenotypic transformation of smooth muscle cells and the formation of new linings after carotid balloon strain in rats, suggesting the importance of PHB2-hnRNPA1 binding in maintaining the constriction phenotype of
vascular smooth muscle.

The team further found that the binding of PHB2 to hnRNPA1 inhibits the shearing of pre-pkm mRNA by hnRNPA1, the expression of PKM2 and the metabolic reprogramming
of smooth muscle cells from oxidative phosphorylation activity to aerobic glycolysis activity.
Finally, the researchers found that PKM2 in vivo knockdown can flip PHB2 knockout on smooth muscle phenotypic transformation and neonatal endometrial formation
.

In summary, the study reveals the important role
of PHB2 in regulating smooth muscle metabolism and phenotype.
PHB2 knockout of smooth muscle cells promotes the formation
of neonatal linings after vascular injury.
Mechanologically, PHB2 inhibits PKM2 expression and aerobic glycolysis induced by binding to hnRNPA1 to maintain the vascular smooth muscle cell contraction phenotype
.
These findings provide new ideas and targets for the treatment of diseases such as restenosis and atherosclerosis
.

Dr.
Yiting Jia and Dr.
Chenfeng Mao of the Department of Physiology and Pathophysiology, Peking University Health Science Center are the co-first authors of this paper, and Professor Kong Wei and Dr.
Jia Yiting of Peking University Health Science Center are co-corresponding authors
of this paper.
The work was completed
in cooperation with Professors Fu Yi, Feng Juan and Zhou Yuan of Peking University Medical College, Professor Xu Qingbo of the First Affiliated Hospital of Zhejiang University School of Medicine, Professor Zhao Ling of Sun Yat-sen University and Professor Chen Jingzhou of Fuwai Hospital of Chinese Academy of Medical Sciences.
The work has also been funded
by the National Natural Science Foundation of China, the Innovation Group Project, and the Youth Fund Project.

Original link:

(School of Basic Medicine, Peking University)