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1 Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA
2 Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA
3 Department of Anesthesia, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ, USA
* To whom correspondence should be addressed. E-mail: hweiss{at}umdnj.edu.
Leptin is a regulator of body weight and affects nitric oxide (NO) production. This study was designed to determine whether the myocardial NO/cGMP signal transduction system was altered in leptin deficient obese mice. Contractile function, guanylyl cyclase activity and cGMP-dependent protein phosphorylation were assessed in ventricular myocytes isolated from ob/ob (B6.V-Lepob) and age-matched lean mice (C57BL/6J). There were no differences in baseline contraction between the lean and obese groups. After stimulation with the NO donor S-nitroso-N-acetyl-penicillamine (SNAP, 10-6 and 10-5M) or a membrane-permeable cyclic GMP analog 8-Bromo-cyclic GMP (8-Br-cGMP, 10-6 and 10-5M), cell contractility was depressed. However, 8-Br-cGMP had significantly greater effects in obese mice than in lean controls with percentage shortening reduced by 47% vs. 39% and maximal rate of shortening by 46% vs. 36%. The negative effects of SNAP were similar between the two groups. Soluble guanylyl cyclase activity was not attenuated. This suggested that the activity of the cGMP-independent NO pathway may be enhanced in obesity. The phosphorylated protein profile of cGMP-dependent protein kinase showed that four proteins were more intensively phosphorylated in obese mice, suggesting an explanation for the enhanced effect of cGMP. These results indicated that the NO-cGMP signaling pathway was significantly altered in ventricular myocytes from the leptin-deficient obese mouse model.
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