Functional thyrotropin receptor expression in the ventricle and the effects on ventricular BNP secretion.
Elevated thyrotropin (TSH) and hypercholesterolemia commonly coexist in patients with subclinical hypothyroidism, which can cause and aggravate heart disease. However, it is unclear whether TSH has a direct effect on cardiac function. To determine the expression of the thyrotropin receptor (TSHR) and the effects of TSH on ventricular function, we analyzed the ventricular tissues and thyroid glands from normal rats and mice and the H9c2 cardiomyocyte cell line. The results revealed that TSHR was expressed at the transcriptional and protein levels by PCR, immunoblotting, immunohistochemistry and immunofluorescence. The mRNA levels of β-MHC and the expression of pCREB and HMGCR in the ventricle were significantly lower in Tshr (-/-) mice than in wild-type (WT) mice (p < 0.05), but serum NT-proBNP levels were similar between WT and Tshr (-/-) mice. After synchronization, H9c2 cells were stimulated with several concentrations of TSH for various time periods. TSH up-regulated β-MHC mRNA expression in H9c2 cells. Cyclic adenosine monophosphate (cAMP) production and downstream signaling, such as pCREB and HMGCR expression and NT-proBNP secretion, increased in dose- and time-dependent manners. The TSH-stimulated effects were suppressed by an adenylyl cyclase inhibitor, a protein kinase A (PKA) inhibitor and HMGCR inhibitors (all p < 0.05). The data indicate functional TSHR is expressed in ventricular myocytes and mediates TSH-induced BNP secretion and HMGCR up-regulation through the cAMP/PKA/pCREB signaling pathway. Our findings suggest a potentially novel pathophysiological role of TSH in heart failure-associated hypothyroidism.
Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, 324 Jing 5 Road, Jinan, Shandong, 250021, China.
Wen
W
Huang
Jin
J
Xu
Fei
F
Jing
Wen-Bin
WB
Chen
Ling
L
Gao
Hai-Tao
HT
Yuan
Jia-Jun
JJ
Zhao
D000818:Animals; D002460:Cell Line; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013972:Thyrotropin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D011989:Receptors, Thyrotropin; D020097:Natriuretic Peptide, Brain; D013972:Thyrotropin; D006903:Hydroxymethylglutaryl CoA Reductases