No abstract

Our results suggest that some alleles of UCP3 are involved in the etiology of human obesity.

This study investigates mechanisms underlying beta3-adrenergic activation of the endothelial nitric oxide synthase (eNOS) in myocardial tissue of wild-type (WT) and beta3-adrenoceptor knockout (beta3-KNO) mice, in the absence and presence of BRL 37344 (BRL), the preferential beta3-adrenoceptor selective agonist. Nitric oxide (NO)-liberation was measured after the application of BRL (10 micromol/L), using fluorescence dye diaminofluorescein (DAF), in left ventricular cardiac preparations. Phosphorylation of eNOSSer1177, eNOSThr495, eNOSSer114, and eNOS translocation, and alterations of 8-isoprostaglandin F2alpha (a parameter for reactive oxygen radical generation), after application of BRL (10 micromol/L), were studied using immunohistochemical stainings in isolated, electrically stimulated (1 Hz) right atrial (RA) and left ventricular (LV) myocardium. An increased NO release after BRL application (10 micromol/L) was observed in the RA and LV myocardial tissue of WT mice, but not in beta3-KNO mice. This NO liberation in WT mice was paralleled by an increased eNOSSer1177, but not eNOSThr495, phosphorylation. A cytosolic eNOS translocation was observed after the application of BRL (10 micromol/L) only in the RA myocardial tissue of WT mice. A BRL (10 micromol/L)-dependent increase in eNOSSer114 phosphorylation was observed only in the LV myocardial tissue of WT mice; this was paralleled by an increase in 8-isoprostaglandin F2alpha. In murine myocardium, 3 beta3-adrenoceptor-dependent activation pathways for eNOS exist (i.e., a translocation and phosphorylation of eNOSSer1177 and eNOSSer114). These pathways are used in a regional-dependent manner. beta3-adrenergic oxygen-derived free radical production might be important in situations of enhanced beta3-adrenoceptor activation, as has been described in human heart failure.

No abstract

This study investigated the influence of chronic beta(3)-adrenoceptor deficiency on myocardial function. Therefore, we investigated Ca(2+)-regulatory proteins, SERCA 2a activity, and myofibrillar and mitochondrial function in hearts of wild-type (WT, n=7) and beta(3)-adrenoceptor knockout mice (beta(3)-KNO, n=7). Morphometric heart analysis showed no difference between WT and beta(3)-KNO. No alterations were observed for the protein expression of the ryanodine receptor or phospholamban. However, in beta(3)-KNO mice, protein expression of SERCA 2a and phospholamban phosphorylation were significantly increased. These changes were accompanied by an increased SERCA 2a activity in beta(3)-KNO. Alterations in phospholamban phosphorylation were independent of alterations in beta(1)/beta(2)-adrenoceptor distribution and protein expression of G proteins in beta(3)-KNO. Measurement of myofibrillar Ca(2+) sensitivity showed no difference in the Ca(2+)/force relation for WT and beta(3)-KNO. The same seems to hold true for mitochondrial function since the protein expressions of cytochrome c, uncoupling protein 3 and cytochrome c oxidase subunit IV were similar in WT and beta(3)-KNO. The conclusion is that depression of beta(3)-adrenergic stimulation may modulate the protein expression of SERCA 2a and phospholamban phosphorylation, thereby improving sarcoplasmic reticulum Ca(2+) uptake. Thus, beta(3)-adrenergic depression may be a therapeutic aim in situations of impaired SERCA 2a activity, e.g. for the treatment of heart failure.