Optimized new Shengmai powder inhibits myocardial fibrosis in heart failure by regulating the rat sarcoma/rapidly accelerated fibrosarcoma/mitogen-activated protein kinase kinase/extracellular regulated protein kinases signaling pathway.

OBJECTIVE: Exploring the effect of Optimized New Shengmai powder (, ONSMP) on myocardial fibrosis in heart failure (HF) based on rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase kinase (MEK)/extracellular regulated protein kinases (ERK) signaling pathway. METHODS: Randomized 70 Sprague-Dawley rats into sham (n = 10) and operation (n = 60) groups, then established the HF rat by ligating the left anterior descending branch of the coronary artery. We randomly divided the operation group rats into the model, ONSMP [including low (L), medium (M), and high (H) dose], and enalapril groups. After the 4-week drug intervention, echocardiography examines the cardiac function and calculates the ratios of the whole/left heart to the rat's body weight. Finally, we observed the degree of myocardial fibrosis by pathological sections, determined myocardium collagen (COL) I and COL Ⅲ content by enzyme-linked immunosorbent assay, detected the mRNA levels of COL I, COL Ⅲ, α-smooth muscle actin (α-SMA), and c-Fos proto-oncogene (c-Fos) by universal real-time, and detected the protein expression of p-RAS, p-RAF, p-MEK1/2, p-ERK1/2, p-ETS-like-1 transcription factor (p-ELK1), p-c-Fos, α-SMA, COL I, and COL Ⅲ by Western blot. RESULTS: ONSMP can effectively improve HF rat's cardiac function, decrease cardiac organ coefficient, COL volume fraction, and COL I/Ⅲ content, down-regulate the mRNA of COL I/Ⅲ, α-SMA and c-Fos, and the protein of p-RAS, p-RAF, p-MEK1/ 2, p-ERK1/2, p-ELK1, c-Fos, COL Ⅰ/Ⅲ, and α-SMA. CONCLUSIONS: ONSMP can effectively reduce myocardial fibrosis in HF rats, and the mechanism may be related to the inhibition of the RAS/RAF/MEK/ERK signaling pathway.

Effects of Optimized New Shengmai Powder in Modulating β1-AR/cAMP/PKA/CREB Signaling Pathway on Myocardial Fibrosis in Rats with Heart Failure / 中国中医药信息杂志

Objective To investigate the effects of Optimized New Shengmai Powder on myocardial fibrosis in rats with heart failure based on the β1-AR/cAMP/PKA/CREB signaling pathway.Methods Totally 50 SD rats were randomly divided into sham-operation group(10 rats)and operation group(40 rats).The left anterior descending coronary artery was ligated to establish a rat model of heart failure.The modeling rats were randomly divided into the model group,the captopril group,and TCM low-and high-dosage groups,with 8 rats in each group.The administration groups received relevant medicine for gavage for 4 weeks.LVEF and LVFS in rats were detected by echocardiography,and measurement of heart and lung mass and calculation of heart and lung organ coefficients were performed,myocardial fibrosis degree was observed by histopathology,serum NT-ProBNP and cAMP,Col Ⅰ,and Col Ⅲcontent in myocardial tissue were detected by ELISA,immunohistochemical was used to detect β1-AR,cAMP positive expression,and Western blot was used to detect the expression of β1-AR/cAMP/PKA/CREB signaling pathway related proteins.Results Compared with the sham-operation group,the LVEF and LVFS of the model group rats were significantly decreased(P<0.01),and the heart and lung organ coefficient significantly increased(P<0.01);the number of myocardial cells decreased,collagen volume fraction increased,and the proportion of type Ⅰ/Ⅲcollagen fibers increased(P<0.01),the contents of serum NT-ProBNP and myocardial tissue Col Ⅰ and Col Ⅲincreased significantly,while the cAMP content in myocardial tissue decreased significantly(P<0.01),the positive expressions of β1-AR and cAMP were significantly decreased(P<0.01),the expressions of β1-AR,AC1,cAMP,p-PKA,and p-CREB proteins were significantly decreased,while protein expressions of p-Smad2,Col Ⅰ,Col Ⅲ,and α-SMA significantly increased(P<0.05,P<0.01).Compared with the model group,the administration groups could increase LVEF and LVFS and decrease heart and lung organ coefficient to different degrees in rats;increase the number of myocardial cells,decrease collagen volume fraction and the proportion of type Ⅰ/Ⅲ collagen fibers,down-regulate serum NT-ProBNP and the content of Col Ⅰ and Col Ⅲ in myocardial tissue,up-regulate the content of cAMP,increase the positive expressions of β1-AR and cAMP in myocardial tissue,up-regulate β1-AR,AC1,cAMP,p-PKA,p-CREB protein expression,and inhibit p-Smad2,Col Ⅰ,Col Ⅲ,and α-SMA protein expression,in which the effects of the TCM high-dosage group and captopril group were more pronounced(P<0.01,P<0.05).Conclusion Optimized New Shengmai Powder can effectively reduce myocardial fibrosis in heart failure rats,improve myocardial hypertrophy and remodeling,and increase left ventricular contractility,and the mechanism may be related to the activation of the β1-AR/cAMP/PKA/CREB signaling pathway.