Thyroid control of sarcolemmal Na+/Ca2+exchanger and SR Ca2+-ATPase in developing rat heart

Cernohorský, J; Kolář, František; Pelouch, V.; Korecký, B.; Vetter, Roland

doi:10.1152/ajpheart.1998.275.1.h264

Cited by 52 publications

(63 citation statements)

References 37 publications

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“…It is interesting to note that the molecular changes observed in our mice overexpressing D2 also occur in the postnatal period as a result of an endogenous TH surge (2,4,23). In contrast, the complex changes observed in heart disease recapitulate the fetal phenotype and mimic hypothyroidism (5,8).…”

Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingmentioning

confidence: 83%

“…This surge is critical for fetal-to-adult switch in the cardiac gene program and is responsible for changes in Ca 2ϩ homeostasis, myosin isozyme content [␣-myosin heavy chain (MHC)-to-␤-MHC switch], and action potential profile (3,4). Intriguingly, the genetic and functional changes associated with heart failure, such as reduced Ca 2ϩ transients and ␣-MHC-to-␤-MHC shifts, which recapitulate the fetal gene program, are also observed in hypothyroidism (5,6).…”

Section: T Hyroid Hormone (Th) Is Essential For Normal Development Inmentioning

confidence: 99%

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Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Trivieri

Oudit

Sah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone (TH) is critical for cardiac development and heart function. In heart disease, TH metabolism is abnormal, and many biochemical and functional alterations mirror hypothyroidism. Although TH therapy has been advocated for treating heart disease, a clear benefit of TH has yet to be established, possibly because of peripheral actions of TH. To assess the potential efficacy of TH in treating heart disease, type 2 deiodinase (D2), which converts the prohormone thyroxine to active triiodothyronine (T3), was expressed transiently in mouse hearts by using the tetracycline transactivator system. Increased cardiac D2 activity led to elevated cardiac T3 levels and to enhanced myocardial contractility, accompanied by increased Ca 2؉ transients and sarcoplasmic reticulum (SR) Ca 2؉ uptake. These phenotypic changes were associated with up-regulation of sarco(endo)plasmic reticulum calcium ATPase (SERCA) 2a expression as well as decreased Na ؉ ͞Ca 2؉ exchanger, ␤-myosin heavy chain, and sarcolipin (SLN) expression. In pressure overload, targeted increases in D2 activity could not block hypertrophy but could completely prevent impaired contractility and SR Ca 2؉ cycling as well as altered expression patterns of SERCA2a, SLN, and other markers of pathological hypertrophy. Our results establish that elevated D2 activity in the heart increases T3 levels and enhances cardiac contractile function while preventing deterioration of cardiac function and altered gene expression after pressure overload.calcium ͉ cardiac hypertrophy ͉ sarcoplasmic reticulum ͉ deiodinase ͉ transgenic mice T hyroid hormone (TH) is essential for normal development in vertebrates (1), with TH levels rising postnatally and peaking in the third week of life (2). This surge is critical for fetal-to-adult switch in the cardiac gene program and is responsible for changes in Ca 2ϩ homeostasis, myosin isozyme content [␣-myosin heavy chain (MHC)-to-␤-MHC switch], and action potential profile (3, 4). Intriguingly, the genetic and functional changes associated with heart failure, such as reduced Ca 2ϩ transients and ␣-MHC-to-␤-MHC shifts, which recapitulate the fetal gene program, are also observed in hypothyroidism (5, 6). In addition, TH metabolism and signaling are abnormal in heart failure (5, 7, 8). For example, circulating and cardiac triiodothyronine (T3) levels (i.e., active TH) are reduced in advanced heart disease, after acute myocardial infarction, and in patients with cardiopulmonary bypass. These T3 changes occur in association with decreased peripheral conversion of thyroxine (T4) into T3 (5, 8) and elevated cardiac deiodinase type 3 (D3) activity (9). TH receptor expression is also altered in pathological hypertrophy (10), and myocardial contractility is impaired in mice lacking TH receptors (11). Not surprisingly, TH and its analogue 3,5-diiodothyropropionic acid (DITPA) have been advocated for treating heart failure (12, 13) and for reversing cardiac dysfunction in patients with hypothyroidism (5), although TH use has been limited by car...

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Section: Effects Of D2 Expression On Cardiac Function and Ca 2؉ Cyclingmentioning

confidence: 83%

Section: T Hyroid Hormone (Th) Is Essential For Normal Development Inmentioning

confidence: 99%

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Trivieri

Oudit

Sah

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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“…37 The reaction medium of 0.2 ml contained 40 mM imidazole (pH 7.0), 100 mM KCl, 5 mM MgCl 2 , 5 mM Tris-ATP, 6 mM phosphocreatine, 10 mM K-oxalate, 0.2 mM ethyleneglycol tetraacetate, 10 mM NaN 3 , 3-4 mg of homogenate protein and 0.034 or 3.68 mM free 45 CaCl 2 (2 Â 10 12 Bq/ mol). For determination of the degree of stimulation of Ca 2+ uptake by PKA-dependent phosphorylation at 0.34 mM free 45 CaCl 2 , either 2 mM synthetic PKA inhibitor peptide (PKI(6-22)amide) or 2 mM catalytic subunit of PKA was added to the uptake medium.…”

Section: Sr Ca 2+ Uptake Measurementsmentioning

confidence: 99%

Highly efficient and specific modulation of cardiac calcium homeostasis by adenovector-derived short hairpin RNA targeting phospholamban

et al. 2006

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Impaired function of the phospholamban (PLB)-regulated sarcoplasmic reticulum Ca 2+ pump (SERCA2a) contributes to cardiac dysfunction in heart failure (HF). PLB downregulation may increase SERCA2a activity and improve cardiac function. Small interfering (si)RNAs mediate efficient gene silencing by RNA interference (RNAi). However, their use for in vivo gene therapy is limited by siRNA instability in plasma and tissues, and by low siRNA transfer rates into target cells. To address these problems, we developed an adenoviral vector (AdV) transcribing short hairpin (sh)RNAs against rat PLB and evaluated its potential to silence the PLB gene and to modulate SERCA2a-mediated Ca 2+ sequestration in primary neonatal rat cardiomyocytes (PNCMs). Over a period of 13 days, vector transduction resulted in stable 499.9% ablation of PLB-mRNA at a multiplicity of infection of 100. PLB protein gradually decreased until day 7 (772% left), whereas SERCA, Na + / Ca 2+ exchanger (NCX1), calsequestrin and troponin I protein remained unchanged. PLB silencing was associated with a marked increase in ATP-dependent oxalate-supported Ca 2+ uptake at 0.34 mM of free Ca 2+ , and rapid loss of responsiveness to protein kinase A-dependent stimulation of Ca 2+ uptake was maintained until day 7. In summary, these results indicate that AdV-derived PLB-shRNA mediates highly efficient, specific and stable PLB gene silencing and modulation of active Ca 2+ sequestration in PNCMs. The availability of the new vector now enables employment of RNAi for the treatment of HF in vivo.

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“…2 B). Prolonged daily treatment of developing hypothyroid rats with doses of T3 Ͼ1 g/gm body wt can compromise the survival of the animals (Cernohorsky et al, 1998). Thus, the effect of a 1 week T3 treatment in MTU-treated rats was analyzed using a dose of 0.05 g/gm body wt.…”

Section: Effects Of T3 Injection On Microglial Developmentmentioning

confidence: 99%

Regulation of Microglial Development: A Novel Role for Thyroid Hormone

et al. 2001

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The postnatal development of rat microglia is marked by an important increase in the number of microglial cells and the growth of their ramified processes. We studied the role of thyroid hormone in microglial development. The distribution and morphology of microglial cells stained with isolectin B4 or monoclonal antibody ED1 were analyzed in cortical and subcortical forebrain regions of developing rats rendered hypothyroid by prenatal and postnatal treatment with methyl-thiouracil. Microglial processes were markedly less abundant in hypothyroid pups than in age-matched normal animals, from postnatal day 4 up to the end of the third postnatal week of life. A delay in process extension and a decrease in the density of microglial cell bodies, as shown by cell counts in the developing cingulate cortex of normal and hypothyroid animals, were responsible for these differences. Conversely, neonatal rat hyperthyroidism, induced by daily injections of 3,5,3Ј-triiodothyronine (T3), accelerated the extension of microglial processes and increased the density of cortical microglial cell bodies above physiological levels during the first postnatal week of life.Reverse transcription-PCR and immunological analyses indicated that cultured cortical ameboid microglial cells expressed the ␣1 and ␤1 isoforms of nuclear thyroid hormone receptors. Consistent with the trophic and morphogenetic effects of thyroid hormone observed in situ, T3 favored the survival of cultured purified microglial cells and the growth of their processes. These results demonstrate that thyroid hormone promotes the growth and morphological differentiation of microglia during development.

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Thyroid control of sarcolemmal Na⁺/Ca²⁺exchanger and SR Ca²⁺-ATPase in developing rat heart

Cited by 52 publications

References 37 publications

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction

Highly efficient and specific modulation of cardiac calcium homeostasis by adenovector-derived short hairpin RNA targeting phospholamban

Regulation of Microglial Development: A Novel Role for Thyroid Hormone

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