Shenmai Injection Improves Hypertensive Heart Failure by Inhibiting Myocardial Fibrosis via TGF-β 1/Smad Pathway Regulation / 中国结合医学杂志

OBJECTIVE@#To study effects of Shenmai Injection on hypertensive heart failure and its mechanism for inhibiting myocardial fibrosis.@*METHODS@#Salt-sensitive (Dahl/SS) rats were fed with normal diet (0.3% NaCl) and the high-salt diet (8% NaCl) to observe the changes in blood pressure and heart function, as the control group and the model group. Salt-insensitive rats (SS-13BN) were fed with the high-salt diet (8% NaCl) as the negative control group. After modeling, the model rats were randomly divided into heart failure (HF) group, Shenmai Injection (SMI) group and pirfenidone (PFD) group by a random number table, with 6 rats in each group. They were given sterilized water, SMI and pirfenidone, respectively. Blood pressure, cardiac function, fibrosis and related molecular expression were detected by sphygmomanometer, echocardiogram, enzyme linked immunosorbent assay (ELISA), hematoxylin-eosin staining, Masson staining, immunofluorescence and qPCR analysis.@*RESULTS@#After high-salt feeding, compared with the control and negative control group, in the model group the blood pressure increased significantly, the left ventricular ejection fraction (LVEF) and left ventricular fraction shortening (LVFS) were significantly reduced, and the serum NT-proBNP concentration increased significantly (all P<0.05); furthermore, the arrangement of myocardial cells was disordered, the edema was severe, and the degree of myocardial fibrosis was also significantly increased (P<0.05); the protein and mRNA expressions of collagen type I (Col I) were up-regulated (P<0.05), and the mRNA expressions of transforming growth factor β 1 (TGF- β 1), Smad2 and Smad3 were significantly up-regulated (P<0.05). Compared with HF group, after intervention of Shenmai Injection, LVEF and LVFS increased, myocardial morphology was improved, collagen volume fraction decreased significantly (P<0.05), and the mRNA expressions of Col I, TGF- β 1, Smad2 and Smad3, as well as Col I protein expression, were all significantly down-regulated (all P<0.05).@*CONCLUSION@#Myocardial fibrosis is the main pathological manifestation of hypertensive heart failure, and Shenmai Injection could inhibit myocardial fibrosis and effectively improve heart failure by regulating TGF-β 1/Smad signaling pathway.

The renal metabolic mechanism of salt sensitive hypertension in Dahl-SS rats / 生理学报

The kidney is one of the main target organs involved in hypertension, and it regulates water and salt metabolism, blood volume and vascular resistance. High salt intake induces salt and water retention, persistent endothelial dysfunction and elevation of blood pressure in salt sensitive individuals. Dahl salt sensitive (Dahl-SS) rats, as a classic animal model for salt sensitive hypertension, have many similar stably inherited physiological characteristics to human with salt sensitive hypertension, such as salt sensitivity, hyperlipidemia, insulin resistance, renal failure, increased urinary protein secretion and low plasma renin activity. Based on renal physiology and biochemistry researches and multi-omics analyses in Dahl-SS rats, this review will summarize the relationship between salt sensitive hypertension and renal redox, NO, amino acids, glucose and lipid metabolism.

Salt-induced epithelial-to-mesenchymal transition in Dahl salt-sensitive rats is dependent on elevated blood pressure

Dietary salt intake has been linked to hypertension and cardiovascular disease. Accumulating evidence has indicated that salt-sensitive individuals on high salt intake are more likely to develop renal fibrosis. Epithelial-to-mesenchymal transition (EMT) participates in the development and progression of renal fibrosis in humans and animals. The objective of this study was to investigate the impact of a high-salt diet on EMT in Dahl salt-sensitive (SS) rats. Twenty-four male SS and consomic SS-13BN rats were randomized to a normal diet or a high-salt diet. After 4 weeks, systolic blood pressure (SBP) and albuminuria were analyzed, and renal fibrosis was histopathologically evaluated. Tubular EMT was evaluated using immunohistochemistry and real-time PCR with E-cadherin and alpha smooth muscle actin (α-SMA). After 4 weeks, SBP and albuminuria were significantly increased in the SS high-salt group compared with the normal diet group. Dietary salt intake induced renal fibrosis and tubular EMT as identified by reduced expression of E-cadherin and enhanced expression of α-SMA in SS rats. Both blood pressure and renal interstitial fibrosis were negatively correlated with E-cadherin but positively correlated with α-SMA. Salt intake induced tubular EMT and renal injury in SS rats, and this relationship might depend on the increase in blood pressure.

Effects of mineral-rich salt intake on the serum and blood pressure of Dahl salt-sensitive rats / 동물의과학연구지

This study was conducted in order to determine the functionality of mineral-rich salt with lower NaCl and higher mineral contents on blood pressure and lipid metabolism in Dahl salt-sensitive rats. A 1% salt solution was administered to five-week-old male Dahl rats- one normal and three salt groups (Purified salt, sun-dried salt, and bamboo salt) for 15 weeks. On the basis of the salt production process, the sun-dried group was classified into two subgroups: SS1 (2-year) and SS2 (>5-year) depending on the storage period of the mineral-rich salt. The relationships between salt intake and changes in blood pressure, serum lipids, and serum mineral concentrations were then examined. The results showed that intake of SS2, which is stored for five years, and BS (bamboo salt) resulted in continuous delay of the increase in blood pressure and inhibited angiotensin-converting enzyme (ACE) activity. In addition, a significant decrease in the triglyceride level in serum lipids of approximately 30% was observed in the SS2 group compared to the PS (purified salt) group. However, all salt intake groups showed an increase in total cholesterol levels compared to the normal group. The results demonstrate that intake of mineral-rich salt is beneficial for the human body and results in reduced blood pressure and triglyceride levels in serum lipids, however, conduct of more research will be needed in order to explore other functions.

Effects of CD40LIg gene-modified bone marrow mesenchymal stem cells on liver graft rejection in rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the effects of cluster of differentiation 40 ligand immunoglobulin (CD40LIg) gene-modified bone marrow mesenchymal stem cells (MSCs) on liver graft rejection in rats.</p><p><b>METHODS</b>The orthotopic liver transplantation models were established with DA rats as the donors and Lewis rats as the recipient. MSCs infected with the recombinant adenoviruses containing CD40LIg gene were infused into the liver graft after transplantation. The liver function, survival of the recipient rats and the morphological changes of the liver grafts were observed after the transplantation. The serum levels of the cytokines interferon-γ (INF-γ) and interleukin-2 (IL-2) in the recipient rats were quantified by ELISA.</p><p><b>RESULTS</b>The survival of the recipient rats receiving transplantation of genetically modified MSCs (group D) was significantly prolonged compared with that of the control group (group A), MSCs group (group B) and gene transfection group (group C); the survival of groups B and C were significantly longer than that of group A (F=7.615, P<0.05). The level of serum alanine aminotransferase, total bilirubin, IL-2 and INF-γ were significantly higher in group A than in the other 3 groups (F=8.738, P<0.05). HE staining of the liver grafts showed severe acute rejection in group A, mild acute graft rejection in groups B and group C, but no rejection in group D.</p><p><b>CONCLUSION</b>CD40LIg gene-modified MSCs can prolong the survival of the recipient rats and suppress graft rejection following liver transplantation.</p>

Effect of puerarin injection on the mRNA expressions of AT1 and ACE2 in spontaneous hypertension rats / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effect of puerarin on angiotensin II type 1 receptor (AT1) and angiotensin-converting enzyme 2 (ACE2) in spontaneous hypertension rat (SHR).</p><p><b>METHODS</b>SHRs, 12 weeks old, were randomly divided into four groups: the model control group (A), the Verapamil group (B), and the two puerarin groups (C and D) treated by low dose and high dose of puerarin respectively. After being treated for 3 weeks, total RNA from tissues of heart, aorta and kidney in rats were extracted and mRNA expression levels of AT1 and ACE2 were determined by RT-PCR.</p><p><b>RESULTS</b>As compared with Group A, the mRNA expressions of AT1 and ACE2 in heart tissue were lower in Group C, and those in kidney tissue were higher in Group D (all P < 0.05); ACE2 mRNA expression was higher in Group D than in Group C (P < 0.05); no significant differences of the two indexes in aorta were shown among various groups. Besides, mRNA expressions of AT1 and ACE2 in heart and kidney tissue were proved to be positively linearly correlated.</p><p><b>CONCLUSION</b>High dose puerarin could increase the mRNA expressions of AT1 and ACE2 in kidney, while low dose puerarin could decrease them in heart; there might be a feed back correlation between AT1 and ACE2.</p>

Association between lysosomal cysteine protease cathepsin's activation and left ventricular function and remodeling in hypertensive heart failure rats / 中华心血管病杂志

<p><b>OBJECTIVE</b>To observe myocardial cathepsin (Cat) S expression and activity in hypertensive heart failure rats.</p><p><b>METHODS</b>The expression and activity of Cat S were determined in the left ventricular (LV) myocardium (LVM) of Dahl salt-sensitive rats fed either a high-salt (HS, 8%) or low-salt (LS, 0, 3%, controls) diet starting at age 7 weeks for 12 weeks (hypertrophy model, H-LVH) or 19 weeks (heart failure model, H-HF). Age-matched rats served as controls and human normal, hypertensive and heart failure myocardial specimen were also examined for changes on the expression and activity of Cat S.</p><p><b>RESULTS</b>Reverse transcription and real-time polymerase chain reaction analysis revealed significantly upregulated Cat S mRNA in rats with H-HF than in rats with H-LVH or in control rats and Cat S mRNA expression is negatively correlated with LVEF (r = -0.88, P < 0.05). In situ and immunohistochemistry examinations showed that Cat S was localized predominantly in cardiac myocytes (CMCs) and coronary vascular smooth muscle cells (SMC). Elastic lamina fragmentations and Cat S-dependent elastolytic activity were significantly increased in H-HF-rats. The expression of interleukin-1 beta was also increased in the LVM of H-HF rats, and this cytokine was found to increase the Cat S protein expression in culture neonatal CMCs. Similar results were revealed in human myocardial specimens.</p><p><b>CONCLUSION</b>Elastolytic Cat S might play an important role in the pathogenesis of myocardial remodeling and heart failure and Cat S might serve as a novel therapeutic target in preventing or reversing hypertension induced LV remodeling and heart failure.</p>

Modelos de hipertensäo arterial / Experimental models of arterial hypertension

Existe uma busca extenuante, por parte dos pesquisadores, de um modelo experimental que possa melhor caracterizar uma patologia täo importante para o ser humano como a hipertensäo essencial. Dentre os modelos genéticos de hipertensäo säo analisados os ratos com hipertensäo espontânea (SHR) e a cepa de ratos sensíveis à ingestäo de sódio (Dahl). Entre os modelos de hipertensäo neurogênica säo discutidos aqueles que envolvem a lesäo do núcleo do trato solitário (NTS), e o da deaferentaçäo sino-aórtica, associada, ou näo, à desnervaçäo das aferências cardiopulmonares. Entre as hipertensöes renais foram destacadas: a renovascular que decorre da oclusäo parcial da artéria renal; a renopriva, como o próprio nome indica; a perinefrítica que decorre da induçäo de fibrose renal pelo envolvimento do rim com um abrasivo contido por um tecido; e liberaçäo do pedículo renal após algumas horas de oclusäo total. O modelo de constriçäo (parcial ou total) da aorta abdominal examina os fatores mecânico e heurohumorais na elevaçäo da pressäo arterial. Um modelo descrito mais recentemente, que é examinado, é o do bloqueio da formaçäo de óxido nítrico (NO) com o L-NAME. E, finalmente, é apresentado o modelo de hipertensäo induzida pelo tratamento com deoxicorticosterona associado à ingestäo alta de sódio.