Thyroid hormone regulation of phospholamban phosphorylation in the rat heart.
Thyroid hormone exerts predictable effects on the contractile performance of the heart in part by regulating the transcription of genes encoding specific calcium transporter proteins. In a rat model of hypothyroidism, left ventricular (LV) contractile function as measured by ejection fraction was decreased by 22% (P < 0.05), and this was returned to control values with T3 treatment. In confirmation of prior studies, LV phospholamban (PLB) protein content was significantly decreased by 25% and 40% compared with hypothyroid LV when the animals were treated with T3 at two doses, 2.5 and 7.0 microg/day, respectively. The ratio of sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2) to PLB protein content was thus increased by 171% and 207%, respectively (P < 0.01). Resolution of the phosphorylated PLB pentamers by SDS-PAGE showed that T3 infusion at 2.5 and 7.0 microg/day decreased (P < 0.001) the amount nonphosphorylated pentamers by 82% and 95%, respectively, in a dose-dependent manner. T3 treatment produced an increase in the proportion of highly phosphorylated PLB pentamers (more than five phosphates) when expressed as a fraction of total pentameric molecules (P < 0.05). Site-specific antibodies showed that the T3-induced increase in phosphorylated PLB pentamers was the result of an increase in both serine 16 and threonine 17 phosphorylation. We conclude that thyroid hormone, in addition to regulating the expression of cardiac PLB, is able to alter the degree of PLB phosphorylation, which correlates with enhancement of LV contractile function. These studies suggest that T3 may augment myocyte calcium cycling via changes in both cAMP- and calcium/calmodulin-dependent protein kinase activities.
Ojamaa
K
K
Department of Medicine, North Shore University Hospital, Manhasset, New York 11030, USA. kojamaa@nshs.edu
Kenessey
A
A
Klein
I
I
D000818:Animals; D002135:Calcium-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000032:analysis / Q000235:genetics; D007037:Hypothyroidism / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011441:Propylthiouracil; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D014284:Triiodothyronine / Q000494:pharmacology*; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D011441:Propylthiouracil; D012333:RNA, Messenger; D014284:Triiodothyronine; D000099211:Phospholamban