tanshinone-ii-a-sodium-sulfonate and Cardiomegaly

The changes of proto-oncogene c-fos and c-jun mRNA expression in angiotensin II (Ang II)-induced hypertrophy and effects of sodium tanshinone IIA sulfonate (STS) in the primary culture of neonatal rat cardiomyocytes were investigated. Twelve neonatal clean grade Wistar rats were selected. The cardiomyocytes were isolated, cultured and divided according to different treatments in the medium. The cardiomyocyte size was determined by phase contrast microscope, and the rate of protein synthesis was measured by [3H]-Leucine incorporation. The c-fos and c-jun mRNA expression in cardiomyocytes was detected by reverse transcription polymerase chain reaction (RT-PCR). It was found after cardiomyocytes were treated with Ang II for 30 min, the c-fos and c-jun mRNA expression in cardiomyocytes was increased significantly (P<0.01). After treatment with Ang II for 24 h, the rate of protein synthesis in Ang II group was significantly increased as compared with control group (P<0.01). After treatment with Ang II for 7 days, the size of cardiomyocytes in Ang II group was increased obviously as compared with control group (P<0.05). After pretreatment with STS or Valsartan before Ang II treatment, both of them could inhibit the above effects of Ang II (P<0.05 or P<0.01). It was suggested that STS could ameliorate Ang II-induced cardiomyocyte hypertrophy by inhibiting c-fos and c-jun mRNA expression and reducing protein synthesis rate of cardiomyocytes.

Topics: Angiotensin II; Animals; Animals, Newborn; Cardiomegaly; Cells, Cultured; Drugs, Chinese Herbal; Myocytes, Cardiac; Phenanthrenes; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Rats; Rats, Wistar; RNA, Messenger

Cardiomyocyte hypertrophy is a major cause of morbidity and mortality worldwide. The aim of this study is to determine the effects of sodium tanshinone IIA sulfonate (STS) on cardiomyocyte hypertrophy induced by angiotensin II (Ang II) in vivo and in vitro. In long-term treatment, adult Wistar rats were infused with Ang II for three weeks via osmotic mini-pumps and some of them were given intragastrically of STS. Left ventricle was isolated; the ratio of left ventricular weight to body weight and systolic blood pressure (SBP) were determined and heart morphometry was assessed after hematoxylin and eosin staining. Results indicated STS inhibited Ang II-induced increases in myocyte diameter and decreased the LVW/BW ratio independent of decreasing systolic blood pressure. In vitro, treatment of cultured cardiomyocytes with STS inhibited Ang II-induced increase in cell size, protein synthesis, ANP expression, activation of extracellular signal- regulated kinase (ERK) and ERK kinase (MEK). Then we reexamined the mechanism of STS-induced anti-hypertrophic effects. Results revealed MEK inhibitor U0126 (20 microM) markedly enhanced STS-induced depressions in [(3)H]leucine incorporation and ANP expression. In conclusion, MEK/ERK pathway plays a significant role in the anti-hypertrophic effects of STS.

Topics: Angiotensin II; Animals; Cardiomegaly; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Molecular Structure; Myocytes, Cardiac; Phenanthrenes; Rats; Rats, Wistar

Sodium tanshinone IIA sulfonate (STS), a derivative of tanshinone IIA, is isolated from the root of Salvia miltiorrhiza known as "Danshen." Although injection of S. miltiorrhiza extract and STS is used widely and successfully in clinics in China for treating cardiovascular diseases, the exact mechanism for its therapeutic basis is poorly understood. The present study was undertaken to characterize the effect of STS on angiotensin II-induced hypertrophy on cultured myocytes and cardiac fibroblasts (nonmyocytes) prepared from neonatal rat hearts. Angiotensin II (1nM) increased protein synthesis and surface area in myocytes, and DNA synthesis and cell number in nonmyocytes, respectively. Exposure of the myocytes to STS (5-80 microM) for 24hr produced no cytotoxicity as evaluated by the 3-[4,5-dimethylthiazol-2-yl]-3,5-diphenylformazan (MTT) assay. Although STS (10 microM) alone showed no effect on the growth of cultured cardiac cells, it markedly suppressed angiotensin II-induced enlargement of cells and [3H]phenylalanine incorporation, proceeding from the induction of immediate early gene (c-jun) expression in myocytes. Furthermore, STS prevented the rise in [Ca(2+)](i) mediated by angiotensin II in myocytes. In contrast, STS (10 microM) was without effect on hyperplasia and c-jun expression induced by angiotensin II in nonmyocytes. The present in vitro findings support the interpretation that STS is a substance that may be beneficial in protecting the myocardium against hypertrophy.

Topics: Angiotensin II; Animals; Cardiomegaly; Cell Division; Cell Survival; Cells, Cultured; Drug Interactions; Heart; Myocardium; Phenanthrenes; Rats; Rats, Wistar; Salvia miltiorrhiza