baohuoside-i and Fibrosis

We aimed to investigate the effects of icariside II (ICS II) on myocardial fibrosis in spontaneously hypertensive rats (SHRs) and to explore the possible mechanisms.. We used SHRs as animal models, and we administered ICS II (4, 8 or 16 mg/kg) orally by gavage for 12 consecutive weeks (Fu et al., Biomed Pharmacother 2018; 100: 64). The left ventricular morphology of the rats was observed using haematoxylin-eosin (HE) staining. The occurrence of myocardial interstitial fibrosis was detected by Masson's trichrome staining. The protein levels of alpha smooth muscle actin (α-SMA), Collagen I, III, matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9, respectively), tissue inhibitor of metalloproteinase 1 (TIMP-1), transforming growth factor-β1 (TGF-β1), phospho-Smad2 (p-Smad2), phospho-Smad3 (p-Smad3) and phospho-p38 (p-p38) were examined by Western blotting.. The results suggested that ICS II improved myocardial interstitial and perivascular collagen deposition and decreased Collagen I/III and α-SMA expression. ICS II (8 and 16 mg/kg) downregulated the expression of MMP-2 and MMP9 and upregulated the expression of TIMP1. In addition, the protein levels of p-Smad2/3, TGF-β1 and p-p38 were decreased by ICS II treatment.. The results suggest that ICS II can inhibit the expression of Collagen I and Collagen III through the MMP/TIMP-1 and TGF-β1/Smad2,3/p-p38 signalling pathways and that it has therapeutic effects on myocardial fibrosis.

Topics: Animals; Cardiomyopathies; Collagen Type I; Collagen Type III; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrosis; Flavonoids; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rats; Rats, Inbred SHR; Rats, Wistar; Signal Transduction; Tissue Inhibitor of Metalloproteinase-1

Inhibition or removal of excess reactive oxygen species can effectively protect cellular function or reduce cell death because oxidative stress is the main cause of cellular damage in many diseases. The flavonoid compound IcarisideII having a slight inhibitory effect on PDE5, is the main active components of epimedium in vivo and has a wide range of pharmacological effects on oxidation and apoptosis. However, whether IcarisideII has the same protective effect on ventricular remodeling in spontaneously hypertensive rats (SHR) is unknown. We found that compared with WKY rats, SHRs exhibited noticeable arterial hypertension. Additionally, echocardiography showed that the diameter of the left ventricle was enlarged, wall thickness was increased, and ejection fraction and short axis shortening rate were reduced. H&E staining demonstrated that SHR cells were disordered and noticeably hypertrophic. Masson trichrome staining revealed significant myocardial fibrosis in the myocardium. Tunel staining indicated that 4.39 times the percent of apoptotic cells were present in SHRs compared to WKY rats. In our study, intra-gastric administration of IcarisideII decreased blood pressure, promoted heart function recovery and improved ventricular remodeling in SHRs. Additionally, it reduced myocardial fibrosis, inhibited myocardial apoptosis, decreased the generation of reactive oxygen species and improved SOD activity. IcarisideII down-regulated the activation of the oxidative stress associated proteins ASK1, p38 and JNK; inhibited the expression of p53, Bax and cleaved-caspase3 in the mitochondrial apoptosis pathway; and up-regulated the expression of Bcl-2. In conclusion, this study indicates that IcarisideII can inhibit myocardial apoptosis and improve left ventricular remodeling in SHRs. It can be inferred that this mechanism may be related to the inhibition of the ASK1-JNK/p38 signaling pathway.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Blood Pressure; Fibrosis; Flavonoids; Heart Ventricles; Hydrogen Peroxide; Hydroxyl Radical; JNK Mitogen-Activated Protein Kinases; Male; Malondialdehyde; MAP Kinase Kinase Kinase 5; MAP Kinase Signaling System; Mitochondria; Myocytes, Cardiac; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Inbred SHR; RNA, Messenger; Superoxide Dismutase; Tumor Suppressor Protein p53; Ventricular Remodeling

Studies have demonstrated that icariin plays important roles in preventing hypertension and improving myocardial hypertrophy, inflammatory and infiltration. Icariside (ICS II) is the main metabolite of icariin, which has anti-inflammatory and anti-oxidant activities and protects against ischaemic brain injury. Whether ICS II improves myocardial fibrosis in spontaneously hypertensive rats (SHRs) and the related mechanism remain unknown. Some studies have suggested that TGF-β and the nuclear factor κB signalling pathway play a key role in the progression of myocardial fibrosis. Therefore, in the current study, we aimed to evaluate the effects of ICS II on induced myocardial fibrosis in SHRs and explore the mechanism underlying this activity. The SHRs were treated with ICS II (4, 8, and 16 mg/kg) via daily gavage for 12 weeks. Left ventricular function was detected using the Vevo2100 system, and the collagen area was measured by Masson staining. The results indicated that ICS II markedly improved left ventricular function and decreased the left ventricular myocardial collagen area compared with the SHR group. To further investigate the mechanism underlying this activity, we measured the protein expression of interleukin-1β (IL-1β), tumour necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), Smad2, inhibitory κB (IκB), and nuclear factor κB (NF-κB) p65 by Western blot. The results showed that ICS II inhibited NF-κB p65 expression and the TGF-β1/Smad2 signalling pathways. In conclusion, the present results suggest that ICS II suppresses myocardial fibrosis in SHRs, and this effect might be at least partially mediated through suppression of NF-kB signalling and the TGF-β1/Smad2 signalling pathway.

Topics: Animals; Blood Pressure; Drugs, Chinese Herbal; Fibrosis; Flavonoids; Hypertension; Male; Myocardium; NF-kappa B; Rats, Inbred SHR; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta1