Effects Of Oligomeric Grape Seed Proanthocyanidins On Cardiovascular Remodeling In DOCA-Salt Induced Hypertension Mice And Its Mechanisms

Objective Cardiovascular remodeling is an important pathological features ofhypertension, which is a strong independent risk factor for cardiovascular diseasemorbidity and mobility increased. Deeply approach the mechanism of cardiovascularremodeling development and to explore new treatment strategy is a research topic ofcardiovascular field in worldwide. This experiment was to investigate whether or notgrape seed proanthocyanidins protect cardiovascular remodeling in mice induced byDOCA and high salt, the antioxidant abilities and signal transcription of GSP were alsostudied.Methods Male Kunming mice (weight range23–26g), were treated with renal arteryligation and resection of the left kidney. Mice were randomly divided into8groups:Control group: double kidneys+sc normal saline (NS); Single kidney control group:uninephrectomized (UnX)+sc NS; model group: UnX+DOCA (sc)-salt; GSP65mg/kggroup; GSP130mg/kg group; GSP195mg/kg group; Amlodipine5mg/kg group andTempol60mg/kg group. DOCA was given subcutaneousl (150mg/kg sc,0.025ml/10g,twice per week for4weeks) and1%saline;0.2%potassium chloride was added totheir tap water for drinking to induce cardiovascular remodeling in mice. The later6group were treated the same as model group. At the same time, the drugs were dissolvedin distilled water and administered orally via a gastric tube. At the end of the experiment,the heart weight index(heart weight／body weight, HW／BW) and kidney weightindex(kidney weight／body weight, KW/BW) were evaluated. The histological changes of heart, thoracic aortic and kidney were investigated by HE and/or Van Giesonstaining. The vasodilation effect on thoracic aortic rings that was induced byacetylcholine (ACh) were investigated by Isolated vascular ring perfusion method.Colorimetric analysis were used to assay SOD activity, MDA content and NO content inserum and hydroxyproline(Hyp) content in cardiac tissue. Western blot method wasused to measure the ASK1、 NF-κB and COX-2protein expression in cardiac tissue.Results Compared with control group of single kidney, the heart weight index, kidneyweight index, cardiomyoctytes cross section area(CSA),cardiac collagen deposition,cardiac Hyp content, media thickness of thoracic aorta, glomerulus area and serumMDA content were increased markedly, as well as ASK-1、 NF-κB and COX-2proteinexpression in cardiac tissue. Serum SOD activity, NO content andendothelial-dependent vasodilation of thoracic aortic rings inducing by acetylcholine(ACh) were decreased significantly. Compared with model group, administration ofGSPs, amlodipine and tempol markedly inhibited the elevation of HW/BW, KW/BWratio, CSA of cardiomyocytes, media thickness of thoracic aorta and glomerulus area,decreased collagen deposition in heart. Meanwhile, treatment with GSPs, amlodipineand tempol significantly ameliorated oxidative stress via improving SOD activities anddecreasing MDA formation. Moreover, treatment with GSPs improved endothelialdysfunction manifesting by promoting endothelial-dependent vasodilation of thoracicaortic rings and enhancing the NO activity in serum. Finally, cardiac ASK-1、 NF-κBand COX-2protein expression were downregulated in a dose-dependent manner afteradministration of GSPs.Conclusion GSP has protective effects against cardiovascular remodeling and kidneyhypertrophy of DOCA-salt induced hypertensive mice, its mechanism may be related tointervening the ROS/ASK-1/NF-κB signal transcription pathways, reducing the oxidative stress, preserving NO biological activity and improving endothelialdysfunction.