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Articles by K Savvatis
Total Records ( 3 ) for K Savvatis
  S Pinkert , D Westermann , X Wang , K Klingel , A Dorner , K Savvatis , T Grossl , S Krohn , C Tschope , H Zeichhardt , K Kotsch , K Weitmann , W Hoffmann , H. P Schultheiss , O. B Spiller , W Poller and H. Fechner
 

Background— Group B coxsackieviruses (CVBs) are the prototypical agents of acute myocarditis and chronic dilated cardiomyopathy, but an effective targeted therapy is still not available. Here, we analyze the therapeutic potential of a soluble (s) virus receptor molecule against CVB3 myocarditis using a gene therapy approach.

Methods and Results— We generated an inducible adenoviral vector (AdG12) for strict drug-dependent delivery of sCAR-Fc, a fusion protein composed of the coxsackievirus-adenovirus receptor (CAR) extracellular domains and the carboxyl terminus of human IgG1-Fc. Decoy receptor expression was strictly doxycycline dependent, with no expression in the absence of an inducer. CVB3 infection of HeLa cells was efficiently blocked by supernatant from AdG12-transduced cells, but only in the presence of doxycycline. After liver-specific transfer, AdG12 (plus doxycycline) significantly improved cardiac contractility and diastolic relaxation compared with a control vector in CVB3-infected mice if sCAR-Fc was induced before infection (left ventricular pressure 59±3.8 versus 45.4±2.7 mm Hg, median 59 versus 45.8 mm Hg, P<0.01; dP/dtmax 3645.1±443.6 versus 2057.9±490.2 mm Hg/s, median 3526.6 versus 2072 mm Hg/s, P<0.01; and dP/dtmin –2125.5±330.5 versus –1310.2±330.3 mm Hg/s, median –2083.7 versus –1295.9 mm Hg/s, P<0.01) and improved contractility if induced concomitantly with infection (left ventricular pressure 76.4±19.2 versus 56.8±10.3 mm Hg, median 74.8 versus 54.4 mm Hg, P<0.05; dP/dtmax 5214.2±1786.2 versus 3011.6±918.3 mm Hg/s, median 5182.1 versus 3106.6 mm Hg/s, P<0.05), respectively. Importantly, hemodynamics of animals treated with AdG12 (plus doxycycline) were similar to uninfected controls. Preinfection induction of sCAR-Fc completely blocked and concomitant induction strongly reduced cardiac CVB3 infection, myocardial injury, and inflammation.

Conclusion— AdG12-mediated sCAR-Fc delivery prevents cardiac dysfunction in CVB3 myocarditis under prophylactic and therapeutic conditions.

  R Knoll , S Kostin , S Klede , K Savvatis , L Klinge , I Stehle , S Gunkel , S Kotter , K Babicz , M Sohns , S Miocic , M Didie , G Knoll , W. H Zimmermann , P Thelen , H Bickeboller , L. S Maier , W Schaper , J Schaper , T Kraft , C Tschope , W. A Linke and K. R. Chien
 

Rationale: We previously discovered the human 10T->C (Trp4Arg) missense mutation in exon 2 of the muscle LIM protein (MLP, CSRP3) gene.

Objective: We sought to study the effects of this single-nucleotide polymorphism in the in vivo situation.

Methods and Results: We now report the generation and detailed analysis of the corresponding MlpW4R/+ and MlpW4R/W4R knock-in animals, which develop an age- and gene dosage–dependent hypertrophic cardiomyopathy and heart failure phenotype, characterized by almost complete loss of contractile reserve under catecholamine induced stress. In addition, evidence for skeletal muscle pathology, which might have implications for human mutation carriers, was observed. Importantly, we found significantly reduced MLP mRNA and MLP protein expression levels in hearts of heterozygous and homozygous W4R-MLP knock-in animals. We also detected a weaker in vitro interaction of telethonin with W4R-MLP than with wild-type MLP. These alterations may contribute to an increased nuclear localization of W4R-MLP, which was observed by immunohistochemistry.

Conclusions: Given the well-known high frequency of this mutation in Caucasians of up to 1%, our data suggest that W4R-MLP might contribute significantly to human cardiovascular disease.

  D Westermann , T Walther , K Savvatis , F Escher , M Sobirey , A Riad , M Bader , H. P Schultheiss and C. Tschope
  OBJECTIVE

Diabetic cardiomyopathy is associated with increased mortality in patients with diabetes. The underlying pathology of this disease is still under discussion. We studied the role of the kinin B1 receptor on the development of experimental diabetic cardiomyopathy.

RESEARCH DESIGN AND METHODS

We utilized B1 receptor knockout mice and investigated cardiac inflammation, fibrosis, and oxidative stress after induction of streptozotocin (STZ)-induced diabetes. Furthermore, the left ventricular function was measured by pressure-volume loops after 8 weeks of diabetes.

RESULTS

B1 receptor knockout mice showed an attenuation of diabetic cardiomyopathy with improved systolic and diastolic function in comparison with diabetic control mice. This was associated with a decreased activation state of the mitogen-activated protein kinase p38, less oxidative stress, as well as normalized cardiac inflammation, shown by fewer invading cells and no increase in matrix metalloproteinase-9 as well as the chemokine CXCL-5. Furthermore, the profibrotic connective tissue growth factor was normalized, leading to a reduction in cardiac fibrosis despite severe hyperglycemia in mice lacking the B1 receptor.

CONCLUSIONS

These findings suggest that the B1 receptor is detrimental in diabetic cardiomyopathy in that it mediates inflammatory and fibrotic processes. These insights might have useful implications on future studies utilizing B1 receptor antagonists for treatment of human diabetic cardiomyopathy.

 
 
 
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