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Articles by S. N Hatem
Total Records ( 2 ) for S. N Hatem
  N Wagner , C Jehl Pietri , P Lopez , J Murdaca , C Giordano , C Schwartz , P Gounon , S. N Hatem , P Grimaldi and K. D. Wagner
  Aims

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors. PPARβ agonists were suggested as potential drugs for the treatment of metabolic syndrome, but effects of PPARβ activation on cardiac growth and vascularization are unknown. Thus, we investigated the consequences of pharmacological PPARβ activation on the heart and the underlying molecular mechanisms.

Methods and results

Male C57/Bl6 mice were injected with the specific PPARβ agonists GW0742 or GW501516, or vehicle. Cardiomyocyte size and vascularisation were determined at different time points. Expression differences were investigated by quantitative reverse transcriptase–polymerase chain reaction and western blotting. In addition, the effects of PPARβ stimulation were compared with hearts of mice undergoing long-term voluntary exercise or pharmacological PPAR activation. Five hours after GW0742 injection, we detected an enhanced angiogenesis compared with vehicle-injected controls. After 24 h, the heart-to-body weight ratios were higher in mice injected with either GW0742 or GW501516 vs. controls. The increased heart size was due to cardiomyocyte enlargement. No signs of pathological cardiac hypertrophy (i.e. apoptosis, fibrosis, or deteriorated cardiac function) could be detected. The effects are mediated via calcineurin A (CnA) activation as: (i) CnA was upregulated, (ii) GW0742 administration or co-transfection of PPARβ significantly stimulated the activity of the CnA promoter, (iii) PPARβ protein bound directly to the CnA promoter, (iv) the CnA target genes NFATc3, Hif-1, and Cdk 9 were upregulated in response to PPARβ stimulation, and (v) the inhibition of CnA activity by cyclosporine A abolished the hypertrophic and angiogenic responses to PPARβ stimulation.

Conclusion

Our data suggest PPARβ pharmacological activation as a novel approach to increase cardiac vascularization and cardiac muscle mass.

  Y Dou , E Balse , A Dehghani Zadeh , T Wang , C. L Goonasekara , G. P Noble , J Eldstrom , D. F Steele , S. N Hatem and D. Fedida
 

The transfection of cardiac myocytes is difficult, and so most of the data regarding the regulation of trafficking and targeting of cardiac ion channels have been obtained using heterologous expression systems. Here we apply the fast biolistic transfection procedure to adult cardiomyocytes to show that biolistically introduced exogenous voltage-gated potassium channel, Kv1.5, is functional and, like endogenous Kv1.5, localizes to the intercalated disc, where it is expressed at the surface of that structure. Transfection efficiency averages 28.2 ± 5.7% of surviving myocytes at 24 h postbombardment. Ventricular myocytes transfected with a tagged Kv1.5 exhibit an increased sustained current component that is ~40% sensitive to 100 µM 4-aminopyridine and which is absent in myocytes transfected with a fluorescent protein-encoding construct alone. Kv1.5 deletion mutations known to reduce the surface expression of the channel in heterologous cells similarly reduce the surface expression in transfected ventricular myocytes, although targeting to the intercalated disc per se is generally unaffected by both NH2- and COOH-terminal deletion mutants. Expressed current levels in wild-type Kv1.5, Kv1.5SH3(1), Kv1.5N209, and Kv1.5N135 mutants were well correlated with apparent surface expression of the channel at the intercalated disc. Our results conclusively demonstrate functionality of channels present at the intercalated disc in native myocytes and identify determinants of trafficking and surface targeting in intact cells. Clearly, biolistic transfection of adult cardiac myocytes will be a valuable method to study the regulation of surface expression of channels in their native environment.

 
 
 
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