ABSTRACT
Cardiovascular diseases (CVDs) and metabolic disorders are major components of noncommunicable diseases, causing an enormous health and economic burden worldwide. There are common risk factors and developmental mechanisms among them, indicating the far-reaching significance in exploring the corresponding therapeutic targets. MST1/2 kinases are well-established proapoptotic effectors that also bidirectionally regulate autophagic activity. Recent studies have demonstrated that MST1/2 influence the outcome of cardiovascular and metabolic diseases by regulating immune inflammation. In addition, drug development against them is in full swing. In this review, we mainly describe the roles and mechanisms of MST1/2 in apoptosis and autophagy in cardiovascular and metabolic events as well as emphasis on the existing evidence for their involvement in immune inflammation. Moreover, we summarize the latest progress of pharmacotherapy targeting MST1/2 and propose a new mode of drug combination therapy, which may be beneficial to seek more effective strategies to prevent and treat CVDs and metabolic disorders.
ABSTRACT
Aim To observe the effects of simvastatin on PPARγ and p65 subunit of NF-κB and to invest the mechanism of simvastatin preventing hypertrophy and keeping cardiac function.Methods 24 rabbits were divided into 4 groups.Rabbits received sham operation as health control in group I. In other groups, aortic regurgitation and coarctation of ascending aorta were operated in rabbits.Rabbits received no drugs in Group Ⅱ. In group Ⅲ, rabbits were given simvastatin 5 mg·kg~(-1)·d~(-1) after the operation for 8 weeks. In group Ⅳ, rabbits were given simvastatin 5 mg·kg~(-1)·d~(-1) after 4 weeks of operation for 4 weeks. At the beginning and the end of the experiment, left ventricular end diastolic pressure (LVEDP) was measured with catheter. At the end of the experiment, heart weight (HW), left ventricular weight (LVW), body weight (BW), heart weight/body weight radio (HW/BW radio), left ventricular weight/body weight radio (LVW/BW radio) were measured.The PPARγ mRNA expression was analyzed by RT-PCR. PPARγ and p65 protein expression in cardiomyocyte nuclear were analyzed through Western blot. The activity of p65 was analyzed with EMSA.Results The HW, LVW, HW/BW were significantly decreased in the early and late treatment group than in CHF group(P<0.05,P<0.01). The LVW/BW was significantly decreased inearly treatment group than in CHF group, too (P<0.01). The LVEDP was significantly decreased in the early and late treatment group than in CHF group (P<0.01). The mRNA and protein of PPARγ significantly fell in CHF heart (P<0.01). The activity and protein expression of p65 were significantly increased in CHF heart (P<0.01). Simvastatin increased the mRNA and protein expression of PPARγ and decreased the activity and protein expression of p65 (P<0.01).Conclusions Simvastatin inhibits the cardiac hypertrophy and improves cardiac function. The mechanism of simvastatin on cardiac remodeling and function relates to the increase of PPARγ expression and preventing the NF-κB activation.
ABSTRACT
Objective Clinical evidence has suggested that ATI receptor blocker (ARB) could prevent the development of heart failure. Decreased sareoplasmic reticulum(SR) Ca2+ content, which is due to reduced SR calcium reuptake by SERCA2a, is responsible for defective systolic function in failing heart. To better understand how ARB could improve cardiac systolic dysfunction, we studied the effects of Valsartan on calcium reuptake of SR and its regulatory proteins in heart failure rabbits. Methods Thirty rabbits were divided into three groups: sham rabbits(controls, n= 11), rabbits with heart failure treated with Valsartan (n= 11) and rabbits with heart failure but without Valsartan treatment (n=8).Rabbit heart failure model was established by volume plus pressure overload. Cardiac function was measured by echocardiography. SR calcium uptake was determined by measuring extra vesicular free [Ca2+] changes in a fluores-cence spectrophotometer. SERCA2a, Serl 6-phosphorylated phospholamban (p-PLB), PKA and PP1a protein abundance were deter-mined by use of Western blot analysis. Results Compared to control rabbits, the ejection fractions in the HF rabbits were significantly decreased (P<0.05), these changes could be significantly attenuated by Valsanan treatment (P<0.05).Calcium reuptake of SR, activity of SERCA2a and PKA decreased in heart failing myocytes (P<0.05), with down regulations of p-PLB, SERCA2a and PKA, but up regulation ofPP1αin ventricular samples from the failing rabbits (P<0.05). All of these changes were attenuated by Valsartan treatment (all P<0.05). Conclusion Valsartan improved cardiac function in volume plus pressure overload induced heart failure of rabbits possibly by restoring the SR calcium uptake resulted from attenuating the activities and expressions of SERCA2a and its regulatory proteins.
ABSTRACT
Objective To compare the differences of cardiac function and interstitial remodeling between diastolic heart failure(DHF) and systolic heart failure(SHF) rabbit models. Methods To establish DHF model with abdo-mial aorta constriction and SHF model with abdomial aorta constriction plus aortic insufficiency. The cardiac func-tion was examined by UCG parameters and homodynamic parameters. The collagen content was measured through hydroxyproline colorimetric assay and shown as collagen area(CA), collagen volume fraction(CVF) and area ratio of Ⅰ to Ⅲ type collagen with PSR. Results Compared with control group, there were significantly increased thick-ness and stiffness of myocardium, impaired diastolic function but normal ejection fraction (EF), and significantly increased collagen content, CA, CVF and area ratio of Ⅰ to Ⅲ type collagen in DHF group; heart chamber was sig-nificantly enlarged, systolic function decreased, and collagen content, CA, CVF significantly increased, but ratio of Ⅰ to Ⅲ type collagen decreased in SHF group(P <0.05 or P <0.01). Conclusion DHF and SHF rabbit mod-els were established successfully, which can simulate clinical profiles and provide technical support to future re-search.
ABSTRACT
0.05) . Four weeks after culture,both transcription factor NKX-2.5 and GATA4 were expressed in the 5-azacytidine group. Additionally,?-mysion heavy chain but not ?-mysion heavy chain expression was observed. CONCLUSION:5-azacytidine induced the differentiation from bone marrow mesenchymal stem cells into myocardial-like cells;in addition,simulated biological microenvironment in both indirect contact group and myocardial cell lysate group also induced the same differentiation. The differentiated cells were cardiac possesses which were between mature cells and cardiac progenitor cells.
ABSTRACT
Objective To study the changes and clinical significance of glutathione redox-state in patients with chronic heart failure.Methods A total of 81 hospitalized CHF patients(NYHA heart function grade from Ⅱ to Ⅳ)and a total of 28 paroxysmal supraventricular(PSVT)patients without other diseases(controlled group)were recruited in Cadiovascular Wards of the First Affiliated Hospital of Suzhou University from Jun.2006 to Mar.2007.The plasma concentration of GSH and GSSG was determined by using glutathione reductase recycling method(GR-DTNB).Redox potential(EhGSH/GSSG)was calculated using Nernst equation according to the concentration of reduced and oxidized glutathione.Results(1)The concentration of GSH was significantly lower in CHF group compared with control group(P