Mechanistic Study on Effect of Cycloastragenol in Improving Mitochondrial Function and Inhibiting Cardiac Remodeling via GPCR/cAMP/PKA/CREB Signaling Pathway
10.13422/j.cnki.syfjx.20260208
- VernacularTitle:基于GPCR/cAMP/PKA/CREB信号通路探讨环黄芪醇改善线粒体功能抑制心脏重构的作用机制
- Author:
Dongsheng WEI
1
;
Menglan ZHAO
1
;
Wenhao GU
1
;
Jinpu LIANG
2
;
Yu LIU
2
;
Xiaoqing ZHANG
1
Author Information
1. School of Life Sciences， Beijing University of Chinese Medicine， Beijing 102401， China
2. Dongzhimen Hospital， Beijing University of Chinese Medicine， Beijing 100700，China
- Publication Type:Journal Article
- Keywords:
cycloastragenol;
heart failure;
G protein-coupled receptor/cyclic adenosine monophosphate/protein kinase A/cAMP response element-binding protein （GPCR/cAMP/PKA/CREB）;
peroxisome proliferator-activated receptor γ coactivator-1α/nuclear respiratory factor 1/mitochondrial transcription factor A （PGC-1α/NRF1/TFAM）;
mitochondrial function;
cardiac remodeling
- From:
Chinese Journal of Experimental Traditional Medical Formulae
2026;32(20):112-121
- CountryChina
- Language:Chinese
-
Abstract:
ObjectiveThis study aimed to evaluate the effects of cycloastragenol （CAG） on mitochondrial dysfunction during cardiac remodeling and to elucidate its regulatory role in myocardial energy metabolic homeostasis and the associated transcriptional regulatory axis. MethodsA rat model of heart failure （HF） was established by ligation of the left anterior descending coronary artery. Rats were randomly divided into a control group， a model group， a captopril group （3.25 mg·kg-1）， a low-dose CAG group （10 mg·kg-1， CAG-L）， and a high-dose CAG group （20 mg·kg-1， CAG-H）. After 28 days of treatment， left ventricular ejection fraction （LVEF）， left ventricular fractional shortening （LVFS）， left ventricular end-diastolic diameter （LVIDd）， and left ventricular end-systolic diameter （LVIDs） were assessed by echocardiography. Serum levels of N-terminal pro-brain natriuretic peptide （NT-proBNP）， creatine kinase-MB （CK-MB）， cardiac troponinⅠ （cTnI）， interleukin-1β （IL-1β）， interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， and cyclic adenosine monophosphate （cAMP） were measured by enzyme-linked immunosorbent assay （ELISA）. Hematoxylin-eosin （HE） and Masson's trichrome staining were used to evaluate myocardial histopathology and fibrosis. Wheat germ agglutinin （WGA）， reactive oxygen species （ROS）， and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling （TUNEL） staining were performed to assess cardiomyocyte hypertrophy， oxidative stress， and apoptosis. Adenosine triphosphate （ATP） content and the activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ were determined by colorimetric assays. The mRNA expression of α-smooth muscle actin （α-SMA）， Col Ⅰ， and Col Ⅲ was detected by Real-time quantitative polymerase chain reaction （Real-time PCR）， while the protein levels of β2-adrenergic receptor （ADRB2）， protein kinase A （PKA）， phosphorylated cAMP response element-binding protein/total cAMP response element-binding protein （p-CREB/CREB）， peroxisome proliferator-activated receptor γ coactivator-1α （PGC-1α）， nuclear respiratory factor 1 （NRF1）， and mitochondrial transcription factor A （TFAM） were analyzed by Western blot. ResultsCompared with the control group， the model group exhibited significantly decreased LVEF， LVFS， and ATP levels （P<0.05）， and markedly increased LVIDd， LVIDs， NT-proBNP， CK-MB， cTnI， IL-1β， IL-6， TNF-α， ROS levels， TUNEL-positive rate， Col deposition area， and the mRNA expression of α-SMA， Col Ⅰ， and Col Ⅲ （P<0.05）. In addition， the activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ， the protein expression of ADRB2， PKA， p-CREB， PGC-1α， NRF1， and TFAM， as well as the cAMP content， were significantly reduced （P<0.05）. Compared with the model group， both low- and high-dose CAG significantly increased LVEF and LVFS， and decreased LVIDd， LVIDs， and the levels of NT-proBNP， CK-MB， and cTnI （P<0.05）. CAG treatment alleviated myocardial disarray and Collagen deposition， and downregulated the mRNA expression of α-SMA， Col Ⅰ， and Col Ⅲ. The treatment markedly reduced ROS generation and the TUNEL-positive rate （P<0.05）， thereby attenuating cardiomyocyte hypertrophy and inflammatory responses. Furthermore， CAG treatment increased ATP content and the activities of mitochondrial respiratory chain complexes Ⅰ-Ⅳ， accompanied by upregulation of PGC-1α， NRF1， TFAM， ADRB2， PKA， and p-CREB protein expression as well as cAMP levels （P<0.05）. The CAG-H group showed the most pronounced improvements， which were superior to those of the captopril group and the CAG-L group. ConclusionCycloastragenol delays adverse cardiac remodeling and improves cardiac function by activating the ADRB2-mediated GPCR/cAMP/PKA/CREB signaling pathway， enhancing the PGC-1α/NRF1/TFAM activity， promoting mitochondrial energy metabolism remodeling， and suppressing oxidative stress， inflammation， and myocardial fibrosis.
