Thyroid hormone receptor alpha1 downregulation in postischemic heart failure progression: the potential role of tissue hypothyroidism.
Thyroid hormone (TH) signaling is altered in response to various stresses including myocardial ischemia. The present study investigated potential implication of TH signaling in the pathophysiology of postischemic remodeling. Acute myocardial infarction was induced in rats by coronary artery ligation (AMI). After 34 weeks, 6 animals were on congestive heart failure (CHF) as indicated by measurements in lung and right ventricular weight. 7 animals were in compensated state (Non-CHF) and 8 sham-operated animals (SHAM) served as controls. Progression to congestive heart failure was characterized by marked decrease in EF% and all other functional echocardiographic parameters. Furthermore, beta-MHC expression was significantly increased in CHF. A distinct pattern of thyroid hormone receptor (TR) expression was observed in the course of postischemic remodeling; TR alpha 1 was upregulated and TR beta 1 was downregulated in Non-CHF, and TR alpha 1 expression was markedly decreased during the transition from Non-CHF to CHF resulting in tissue hypothyroidism. Circulating T3 and T4 remained unchanged. This response was associated with marked decrease in mTOR activation. A potential link between mTOR and TR alpha 1 expression was shown in a neonatal cardiomyocytes model of PE (phenylephrine)-induced pathological growth. Phenylephrine increased the expression of TR alpha 1 in nucleus and this response was abrogated in the case of mTOR inhibition by rapamycin. In conclusion, progression to congestive heart failure after myocardial infarction is associated with suppressed expression of TR alpha 1 and results in tissue hypothyroidism. This process may, at least in part, be mTOR dependent.
Pantos
C
C
Department of Pharmacology, University of Athens, Goudi, Athens, Greece. cpantos@med.uoa.gr
Mourouzis
I
I
Galanopoulos
G
G
Gavra
M
M
Perimenis
P
P
Spanou
D
D
Cokkinos
D V
DV
D000818:Animals; D000831:Animals, Newborn; D018450:Disease Progression; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006333:Heart Failure / Q000097:blood / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology*; D007037:Hypothyroidism / Q000097:blood / Q000150:complications*; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000150:complications; D017202:Myocardial Ischemia / Q000097:blood / Q000150:complications* / Q000000981:diagnostic imaging; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology; D009218:Myosins / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism*; D013963:Thyroid Hormones / Q000097:blood; D014463:Ultrasonography
D020033:Protein Isoforms; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D010656:Phenylephrine; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D009218:Myosins