Cheng  Fang,Feixue  Dong,Liangyou  Zhao,Yongwu  Liu,Na  Zhang,Shumin  Liu,
Exogenous Hydrogen Sulfide Alleviated Left Ventricular Fibrosis Via Enhancing Cardiac Autophagy and Decreasing Cardiomyocyte Apoptosis in StreptozotocinInduced Diabetic Rats: From Network Pharmacology to Experimental Pharmacology
Journal of Diabetes Metabolism and its Complications
2020
2674-4163
http://dx.doi.org/10.31487/j.JDMC.2020.02.05
https://www.sciencerepository.org/exogenous-hydrogen-sulfide-alleviated-left-ventricular-fibrosis-via-enhancing_JDMC-2020-2-105 
Abstract: Streptozotocin (STZ)-induced diabetes mellitus (DM) model shows the signal of cardiac dysfunction,
which is manifested as myocardial fibrosis and hypertrophy. This study was designed to predict targets
of sodium hydrosulfide (NaHS) for diabetic cardiomyopathy and its corresponding triggered pathways
by network pharmacology analysis and test the effects of NaHS as well as its mechanism as possible
modulators of left ventricular remodeling in diabetic rats. The drug-target networks were constructed via
approaches of network pharmacology, and the predicted targets and pathways were validated by in vivo
experiments. Rats were randomly divided into 3 groups (n=6/group): STZ-induced DM group (STZDM); STZ-induced DM treated with H2S group (STZ-NaHS); control group. The control group was
treated with daily saline (i.p.); the diabetic model was induced by intraperitoneal (i.p.) injections of 40
mg/kg/day STZ. After 12 weeks, the rat cardiac function was determined, and the pathological
morphology of the heart was analysed by Masson trichrome staining in each group. The expression level
of matrix metalloproteinase 9 (AGEs), CSE, CBS and several autophagy associated proteins were
detected by the ELISA analysis. Results from the PPI network implied that 27 targets were key regulators.
The AGE-RAGE signaling pathway in diabetic complications and the apoptotic signaling pathway was
discovered to be the key to anti-diabetic cardiomyopathy of NaHS upon the GO enrichment analyses and
KEGG pathway. In the in vivo experiment, compared with the control group, cardiac fibrosis and
attenuated left ventricular function were observed. Furthermore, compared with the control group, the
expression level of CSE, CBS and autophagy associated proteins Atg5 was significantly decreased, while
that of AGEs, autophagy associated proteins p62 and p-ERK1/2 was significantly increased in the STZDM group (P<0.05). In the STZ-NaHS group, cardiac fibrosis and ventricular dysfunction were
ameliorated, the expression level of CSE, CBS and autophagy associated proteins Atg5 was increased,
and the expression level of AGEs, autophagy associated proteins p62 and p-ERK1/2 was significantly
decreased (P<0.05). In conclusion, H2S may alleviate cardiac fibrosis of the STZ-induced DM rat model
by enhancing cardiac autophagy, inhibiting cardiomyocyte apoptosis and downregulating p-ERK1/2.Keywords: Network pharmacology, diabetes mellitus, H2S, autophagy, apoptosis