Thyroid hormone-induced overexpression of functional ryanodine receptors in the rabbit heart.
Modifications in the Ca(2+)-uptake and -release functions of the sarcoplasmic reticulum (SR) may be a major component of the mechanisms underlying thyroid state-dependent alterations in heart rate, myocardial contractility, and metabolism. We investigated the influence of hyperthyroid state on the expression and functional properties of the ryanodine receptor (RyR), a major protein in the junctional SR (JSR), which mediates Ca(2+) release to trigger muscle contraction. Experiments were performed using homogenates and JSR vesicles derived from ventricular myocardium of euthyroid and hyperthyroid rabbits. Hyperthyroidism, with attendant cardiac hypertrophy, was induced by the injection of L-thyroxine (200 microg/kg body wt) daily for 7 days. Western blotting analysis using cardiac RyR-specific antibody revealed a significant increase (>50%) in the relative amount of RyR in the hyperthyroid compared with euthyroid rabbits. Ca(2+)-dependent, high-affinity [(3)H]ryanodine binding was also significantly greater ( approximately 40%) in JSR from hyperthyroid rabbits. The Ca(2+ )sensitivity of [(3)H]ryanodine binding and the dissociation constant for [(3)H]ryanodine did not differ significantly between euthyroid and hyperthyroid hearts. Measurement of Ca(2+)-release rates from passively Ca(2+)-preloaded JSR vesicles and assessment of the effect of RyR-Ca(2+)-release channel (CRC) blockade on active Ca(2+)-uptake rates revealed significantly enhanced (>2-fold) CRC activity in the hyperthyroid, compared with euthyroid, JSR. These results demonstrate overexpression of functional RyR in thyroid hormone-induced cardiac hypertrophy. Relative abundance of RyR may be responsible, in part, for the changes in SR Ca(2+) release, cytosolic Ca(2+) transient, and cardiac systolic function associated with thyroid hormone-induced cardiac hypertrophy.
Jiang
M
M
Department of Physiology, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
Xu
A
A
Tokmakejian
S
S
Narayanan
N
N
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D006332:Cardiomegaly / Q000139:chemically induced / Q000378:metabolism; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology; D006980:Hyperthyroidism / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009929:Organ Size / Q000187:drug effects; D020033:Protein Isoforms / Q000096:biosynthesis; D011817:Rabbits; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis*; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood* / Q000494:pharmacology; D014284:Triiodothyronine / Q000097:blood
D002121:Calcium Channel Blockers; D020033:Protein Isoforms; D019837:Ryanodine Receptor Calcium Release Channel; D014284:Triiodothyronine; D012433:Ryanodine; D013972:Thyrotropin; D013974:Thyroxine; D002118:Calcium