Increased Ca2+ sensitivity and protein expression of SERCA 2a in situations of chronic β3-adrenoceptor deficiency

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.

Moderate intensity of regular exercise improves cardiac SR Ca2+ uptake activity in ovariectomized rats

“…Although there was no evidence of the effect of exercise training on PLB oligomerization status, nevertheless our data clearly demonstrated the effectiveness of regular exercise on maintaining monomer-pentamer equilibrium of PLB after ovarian sex hormone deficiency. Our findings that exercise training increased phospho-Thr 17 and pentameric PLB levels in ovariectomized rat heart provide additional information to the general concept (26,39) in explaining exerciseinduced restoration of SR Ca 2ϩ uptake sensitivity.…”

Beta 3-adrenoreceptor regulation of nitric oxide in the cardiovascular system

“…β3 -/- mice have been shown to have increased SERCA 2a expression in combination with increased phosphorylation of phospholamban, resulting in an increased SERCA 2a activity 109. Therefore, it has been proposed that β3-AR overexpression in heart failure may depress SERCA 2a activity and reduce SR Ca 2+ uptake and contribute to cardiac function loss.…”

β 3 Adrenergic Stimulation of the Cardiac Na + -K + Pump by Reversal of an Inhibitory Oxidative Modification

“…2,6,[11][12][13][14] It has been proposed that blockade of ␤ 3 AR activation in heart failure might be beneficial. 6,[15][16][17] Because the Na ϩ -K ϩ pump effectively is the only export route for the excess intracellular Na ϩ , the therapeutic success of such an approach might be critically dependent on the effect of ␤ 3 AR activation on pump activity. We examined whether ␤ 3 AR activation regulates the Na ϩ -K ϩ pump in ventricular myocytes and alters glutathionylation of the ␤ 1 subunit of the pump, an oxidative modification that is causally related to pump inhibition.…”