Thyroid hormone-induced alterations in phospholamban protein expression. Regulatory effects on sarcoplasmic reticulum Ca2+ transport and myocardial relaxation.

Kiss, Éva; Jakab, G; Kranias, Evangelia G.; Édes, István

doi:10.1161/01.res.75.2.245

Cited by 233 publications

(160 citation statements)

References 27 publications

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“…For example, ET-1 produces a Ͼ50% increase in the amplitude of calcium transients, perhaps via an effect on the Na͞Ca exchanger (26), the Na͞H exchanger (27), or the L-type calcium channel (28). T3 regulates several proteins involved in intracellular calcium metabolism, including the sarcoplasmic reticulum Ca 2ϩ -ATPase (29) and its regulator phospholamban (30,31), Ca 2ϩ channels (32), the ryanodine receptor (33), and protein kinase C (34). If the principal hypertrophic stimulus of T3 is mediated by changes in cytosolic calcium concentration or flux, then it seems likely that the effect of ET-1 on systolic calcium transients could be the mechanism of its action in facilitating T3-induced hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Shohet

Kisanuki

Zhao

et al. 2004

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

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Endothelin 1 (ET-1), a potent vasoconstrictor peptide expressed by endothelium, is also produced in the heart in response to a variety of stresses. It induces hypertrophy in cultured cardiac myocytes but only at concentrations far greater than those found in plasma. We tested whether ET-1 generated by cardiac myocytes in vivo is a local signal for cardiac hypertrophy. To avoid the perinatal lethality seen in systemic ET-1-null mice, we used the Cre͞loxP system to generate mice with cardiac myocyte-specific disruption of the ET-1 gene. We used the ␣-myosin heavy chain promoter to drive expression of Cre and were able to obtain 75% reduction in ET-1 mRNA in cardiac myocytes isolated from these mice at baseline and after stimulation, in vivo, for 24 h with tri-iodothyronine (T3). Necropsy measurements of cardiac mass indexed for body weight showed a 57% reduction in cardiac hypertrophy in response to 16 days of exogenous T3 in mice homozygous for the disrupted ET-1 allele compared to siblings with an intact ET-1 gene. Moreover, in vivo MRI showed only a 3% increase in left ventricular mass indexed for body weight in mice with the disrupted allele after 3 weeks of T3 treatment versus a 27% increase in mice with an intact ET-1 gene. A reduced hypertrophic response was confirmed by planimetry of cardiac myocytes. We conclude that ET-1, produced locally by cardiac myocytes, and acting in a paracrine͞autocrine manner, is an important signal for myocardial hypertrophy that facilitates the response to thyroid hormone. C ardiac hypertrophy is characterized by an increase in myocardiocyte size and is accompanied by qualitative and quantitative changes in gene expression, protein synthesis, and physiological performance (1). Cardiac hypertrophy helps to maintain cardiac output in the presence of increased demand or afterload, yet it is one of the most important predisposing risk factors for sudden death and the development of heart failure in human populations. A greater understanding of hypertrophy, and the capacity to regulate it in human disease, could have profound clinical implications.Many ligand͞receptor systems, with their specific and interwoven downstream signaling pathways, have been implicated in cardiomyocyte hypertrophy in both cell culture and intact animals (reviewed in ref.2). These include the peptide endothelin 1 (ET-1) and its receptors ET A and ET B on the cell surface of cardiomyocytes. Several lines of evidence suggest that ET-1 functions in a paracrine͞autocrine manner in cardiac hypertrophy. In cell cultures of cardiomyocytes, ET-1 induces hypertrophy as assessed by cell size, increased myofibrillogenesis, and transcriptional changes associated with cardiac hypertrophy such as expression of atrial natriuretic factor (3, 4). Of note, in these studies the concentrations of ET-1 required to produce hypertrophy were 10 Ϫ7 to 10 Ϫ9 M, far greater than those encountered in plasma (10 Ϫ12 to 10 Ϫ13 M) (5). Although cardiac synthesis of ET-1 is negligible under normal circumstances, conditions that stimulate...

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Section: Discussionmentioning

confidence: 99%

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Shohet

Kisanuki

Zhao

et al. 2004

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

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“…Thyroid hormone levels have been shown to modulate SR function by altering the expression of SERCA and its regulators. In hyperthyroidism, a decrease in both inhibitors PLB [6,[32][33][34] and SLN [36] relative to SERCA2a is seen. In hypothyroidic hearts, SERCA levels are decreased, whereas PLB and SLN levels are unchanged [6,32,33,36].…”

Section: Sln and Plb Are Differentially Expressed During Development mentioning

confidence: 99%

Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

Bhupathy¹,

Babu²,

Periasamy³

2007

Journal of Molecular and Cellular Cardiology

119

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The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a critical role in maintaining the intracellular calcium homeostasis during cardiac contraction and relaxation. It has been well documented over the years that altered expression and activity of SERCA2a can lead to systolic and diastolic dysfunction. The activity of SERCA2a is regulated by two structurally similar proteins, phospholamban (PLB) and sarcolipin (SLN). Although, the relevance of PLB has been extensively studied over the years, the role SLN in cardiac physiology is an emerging field of study. This review focuses on the advances in the understanding of the regulation of SERCA2a by SLN and PLB. In particular, it highlights the similarities and differences between the two proteins and their roles in cardiac patho-physiology.

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“…These haemodynamic changes cause an increase in cardiac work that leads, in time, to cardiac hypertrophy (16). Furthermore, thyroid hormones have been demonstrated to regulate genes that encode both structural and regulatory proteins in the heart, with an increase in myocardial contractility (17). In fact, in the heart thyroid hormones directly alter the expression of alpha-myosin heavy chain, which has greater ATPase activity than betamyosin heavy-chain (18,19).…”

Section: Cardiac Structure and Functionmentioning

confidence: 99%

“…-ATPase (SERCA2) and phospholamban is regulated by T 3 , acting through changes in gene transcription (17,20). The thyroid hormone-induced changes in SERCA2 protein concentrations are inversely related to alteration in the concentrations of the SERCA2 inhibitor protein, phospholamban.…”

Section: +mentioning

confidence: 99%

“…The thyroid hormone-induced changes in SERCA2 protein concentrations are inversely related to alteration in the concentrations of the SERCA2 inhibitor protein, phospholamban. On the basis of these observations, it has been suggested that thyroid hormone-mediated changes in the relative ratio of phospholamban to Ca 2+ -ATPase regulate the Ca 2+ uptake rates by the reticulum and the relaxation properties of the myocardium (17). Release of calcium and its reuptake into the sarcoplasmic reticulum are critical determinants of systolic contractile function and diastolic relaxation, and explain the changes in contractility and the increased diastolic function in patients with hyperthyroidism (21).…”

Section: +mentioning

confidence: 99%

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Cardiovascular haemodynamics and cardiac autonomic control in patients with subclinical and overt hyperthyroidism

Petretta¹,

Bonaduce²,

Spinelli³

et al. 2001

European Journal of Endocrinology

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Objective: To characterize cardiac structure and function and cardiac autonomic control in patients with subclinical and overt hyperthyroidism. Design: Thirty patients with subclinical hyperthyroidism and 30 with overt disease were selected from patients never previously treated for endocrinological disease in the outpatient clinic of our institution. Twenty normal individuals were studied as control group. Methods: Left ventricular structure and function and cardiac autonomic control were evaluated, respectively, by two-dimensional Doppler echocardiography and by 24-h Holter recording with heart rate variability analysis. Results: Patients with overt hyperthyroidism showed greater values of left ventricular end-diastolic volume P , 0X05 and left ventricular mass P , 0X05 than patients with subclinical disease. In addition, the mean velocity of left ventricular ®bre shortening P , 0X05 and left ventricular ejection fraction P , 0X05 were greater in patients with overt hyperthyroidism than in patients with subclinical disease. No difference in any of these parameters was detectable between normal subjects and patients with subclinical disease. The isovolumic relaxation period was shorter in patients with subclinical hyperthyroidism than in control individuals P , 0X05 and in patients with overt hyperthyroidism P , 0X05. As regards cardiac autonomic control, all time and frequency domain measures decreased progressively from control individuals to patients with subclinical hyperthyroidism and those with overt disease P , 0X001. Conclusions: Thyrotoxic patients show changes in left ventricular structure and increased echocardiographic indexes of myocardial contractility, whereas the only echocardiographic feature detectable in patients with subclinical hyperthyroidism is an increased velocity of left ventricular relaxation. Cardiac parasympathetic withdrawal is evident in patients with overt hyperthyroidism and in patients with subclinical disease.

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Thyroid hormone-induced alterations in phospholamban protein expression. Regulatory effects on sarcoplasmic reticulum Ca2+ transport and myocardial relaxation.

Cited by 233 publications

References 27 publications

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Mice with cardiomyocyte-specific disruption of the endothelin-1 gene are resistant to hyperthyroid cardiac hypertrophy

Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

Cardiovascular haemodynamics and cardiac autonomic control in patients with subclinical and overt hyperthyroidism

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