| Despite significant advances in medical and surgical approaches to treat coronary artery disease in recent years,it remains and will continue to be the most important healthcare challenge of the 21st century.Myocardial infarction(MI),a common Ischemic cardiomyopathy,is typified by the irreversible loss of cardiomyocytes and Supplement and replacement of the necrosed or apoptotic cardiomyocytes after MI has been an unrealistic therapeutic ideal until recently.Although the concept of regeneration of cardiomyocytes remains controversial in the latest years,Beltrami et al and others have provided evidence that a population of myocytes within the myocardium can and does replicate after infarction,challenging the dogma that the heart is a postmitotic nonregenerating organ.The location of the newly regenerated cardiac myocytes occurs exclusively in the border zone adjacent to the infarct and in remote tissues where the blood supply is largely maintained.In addition,recent studies also have shown that the injured myocardium is rich in cytokines and growth factors,which promotes extra-cardiac stem cell migration to the site of the injury as a part of the intrinsic repair process of the injured myocardium.Angiogenesis is the growth of neovessels from existing vasculature and a physiological response to ischemia.Usually,angiogenesis is tightly controlled by a balance of angiogenesis factors and inhibitors,and occurs only in embryonic development,wound healing and the female reproductive cycle.In animal models of ischemia,a growing body of evidence indicates that treatment with angiogenic growth factors can augment nutrients perfusion through neovascularization.To date,the stimulation of angiogenesis using angiogenesis peptides has produced encouraging clinical results in treating coronary artery disease.Although previous clinical trials reported that the administration of angiogenic growth factors as a recombinant protein or gene could enhance the formation of new collateral circulations,relieving some ischemic symptoms,the clinical efficacy of administration of a single growth factor is still highly controversial.In addition,animal and clinical studies demonstrated that transplanted bone marrow cells,adipose stromal cells or endothelial progenitor cells (EPCs)promoted formation of collateral vessels in ischemic tissues by differentiating into vascular cells and/or by secreting angiogenic cytokines.However,bone marrow aspiration and cell transplantation is an invasive procedure that can not be performed frequently.Furthermore,although EPCs could be mobilized into the systemic circulation by cytokines,the safety of the procedure is also still highly controversial. Thus,alternative strategies of manipulation of stem cells or progenitors for therapeutic angiogenesis and myogenesis after MI have been desired.In addition,Considerable evidences suggest that oxidant stress plays a major role in the progression of HF from MI.It may contribute to post-MI progression via numerous mechanisms,of which direct cytotoxic,negative inotropic,cytokine stimulating and apoptotic effects are but a few.Singal et al have shown that occurrence of oxidative stress coincides with the appearance of hemodynamic abnormalities after MI in rats.In that post-MI model,therapy with the anti-oxidant vitamin E helped prevent progressive myocardial dysfunction,a finding that was related to the maintenance of a more normal endogenous anti-oxidant status of the heart.More recently,kinugawa et al demonstrated that the powerful anti-oxidant,dimethylthiourea (DMTU)started 4 h after MI preserved ventricular function,attenuated ventricular dilation,reduced cardiac fibrosis and attenuated the increase in myocardial matrix metalloproteinase-2 activity that normally occurs after MI.Medicinal herbals have been used for thousand years to prevent and manage ischemic heart diseases in traditional Chinese medicine(TCM)practice.In comparison with synthesized chemical medicines,these natural products were widely believed to display little toxicity and few side-effects.DanShen,the rhizome of Salvia-miltiorrhiza Bunge,is one of the most important ancient Chinese herbs and is ranked as "supergrade" medicine in Shen-Nung's Pen-Ts'ao.Because of its properties of improving microcirculation,causing coronary vasodilatation,suppressing the formation of thromboxane,inhibiting platelet adhesion and aggregation,danshen has been widely used in China and,to lesser extent,in Japan,the United States,and other European countries for the treatment of cardiovascular and cerebrovascular diseases.In China,the specific clinical use is angina pectoris,hyperlipidemia,and acute ischemic stroke. Although numerous clinical trials in china have demonstrated that certain Danshen products are effective and safe for the treatment of cardiovascular diseases,most of these lack sufficient quality.Therefore,large randomized clinical trials and further scientific research to determine its mechanism of actions will be necessary to ensure the safety,effectiveness,and better understanding of its actions.Previous studies showed that the Salvia miltiorrhiza extract has good cardio-protective effects on myocardial ischemia in acute phase in rats,but there is little information about its therapeutical potential in chronic phase of ischemic heart diseases. In this investigation,we isolated and purified a fraction mainly containing 3 active components from the Chinese herb salvia miltiorrhiza,and evaluated its therapeutic effects on large MI in rats.To probe its mechanisms involved in,we designed two experiments to explore whether its actions are subjected to anti-oxidative activities or promoting myogenesis and angiogenesis. In current study,we isolated and purified a fraction mainly containing 3 active components from the Chinese herb salvia miltiorrhiza.Myocardial infarction(MI)was induced by ligation of the left anterior descending coronary artery in rats.Rats in treated group were administered with PFSME(200 and 100mg/kg/d)for 4weeks after the surgery.Infarct size,HW/BW ratio,and hemodynamic parameters including MAP, LVEDP and LV _dp/dtmax in the closed-chest preparation were measured.Activity of superoxide dismutase(SOD),glutathione perioxidase(GSH-Px)in the Left ventricular tissue and serum were also detected.In addition,the high levels of malondialdehyde (MDA)in serum and endothelin-1(ET-1)in the plasma and the Left ventricular tissue were examined.Results:Rats in treatment groups were administered with PFSME(200 and 100mg/kg/d)for 4weeks after the surgery.In contrast to MI control group,administration with DanShen (200 and 100mg/kg/d)significantly decreased heart weight index,reduced infarct size, prevented left ventficular remoldeling and improved heart function.The high levels of endothelin-1(ET-1)and malondialdehyde(MDA)in the blood were markedly reduced, and the PFSME treatment also helpful in maintaining the activity of superoxide dismutase(SOD),glutathione perioxidase(GSH-Px)in the Left ventricular tissue and serum at near normality.The study shows clearly that DanShen had good cardio-protective effects in the large myocardial infarction rats,and provides scientific supports for the use of DanShen in Traditional Chinese Medicine practice.Some principles from DanShen hold promise as potential agent for chronic ischemic heart disorders. Experimentâ…¡:A purified fraction of salvia miltiorrhiza extract improves heart function and inhibits ventricular remolding by angiogenesis and myogenesis in ratsAim:To assess the effects of the purified fraction of the salvia miltiorrhiza extract (PFSME)on both angiogenesis and myogenesis after acute MIMethod:In present study,we isolated and purified a fraction mainly containing 3 active components from the Chinese herb salvia miltiorrhiza.Myocardial infarction(MI)was induced by ligation of the left anterior descending coronary artery in rats.Before sacrifice,heart function of all rats was examined by hemodynamic measurements. Morphological parameters such as HW/BW ratio,infarct size(IS),infarct length(IL), circumference and inner diameter of left ventricle(LVC and LVD,respectively)were determined by Masson's trichrome staining.Angiogenesis was verified by measurements of blood vessel density and confirmed by VEGF expression. Cardiomyocytes regeneration was visualized by immunohistochemistry of ki-67 expression.Results:This bioactive fraction displayed favorable dual actions on early angiogenesis and myogenesis in rat model of acute myocardial infarction.Our results demonstrated that oral administration with this bioactive fraction showed pronounced effects on limiting infarct size,stimulating early development of new blood vessels and regenerating cardiomyocytes evidenced by increased ki-67 positive cells with the phenotype of cardiac myocytes in myocardium.Hemodynamic studies showed marked improvement of left ventricular function within 24 hours after coronary occlusion,and the improvement was sustained for 2 months.Morphological analysis also suggested significant amelioration of cardiac remolding by measurements of heart weight index, ventricular dilation and collagen volume deposition in non-infarct area.Conclusion1.PFSME exhibited good cardio-protective effects on large myocardial infarction in rats.2.PFSME antagonized oxidative stress following large MI,protecting infracted myocardium.3.PFSME improved heart function and inhibited left ventricular remolding following large MI,and the mechanisms involved in are attributed to angiogenesis and myocardial regeneration.
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