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      Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac remodelling in rats

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          Abstract

          3,5,3′-Levo-triiodothyronine (L-T3) is essential for DNA transcription, mitochondrial biogenesis and respiration, but its circulating levels rapidly decrease after myocardial infarction (MI). The main aim of our study was to test whether an early and sustained normalization of L-T3 serum levels after MI exerts myocardial protective effects through a mitochondrial preservation. Seventy-two hours after MI induced by anterior interventricular artery ligation, rats were infused with synthetic L-T3 (1.2 μg/kg/day) or saline over 4 weeks. Compared to saline, L-T3 infusion restored FT3 serum levels at euthyroid state (3.0 ± 0.2 versus 4.2 ± 0.3 pg/ml), improved left ventricular (LV) ejection fraction (39.5 ± 2.5 versus 65.5 ± 6.9%), preserved LV end-systolic wall thickening in the peri-infarct zone (6.34 ± 3.1 versus 33.7 ± 6.21%) and reduced LV infarct-scar size by approximately 50% (all P < 0.05). Moreover, L-T3 significantly increased angiogenesis and cell survival and enhanced the expression of nuclear-encoded transcription factors involved in these processes. Finally, L-T3 significantly increased the expression of factors involved in mitochondrial DNA transcription and biogenesis, such as hypoxic inducible factor-1α, mitochondrial transcription factor A and peroxisome proliferator activated receptor γ coactivator-1α, in the LV peri-infarct zone. To further explore mechanisms of L-T3 protective effects, we exposed isolated neonatal cardiomyocytes to H 2O 2 and found that L-T3 rescued mitochondrial biogenesis and function and protected against cell death via a mitoKATP dependent pathway. Early and sustained physiological restoration of circulating L-T3 levels after MI halves infarct scar size and prevents the progression towards heart failure. This beneficial effect is likely due to enhanced capillary formation and mitochondrial protection.

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          Most cited references51

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          Thyroid hormone action in the heart.

          The heart is a major target organ for thyroid hormone action, and marked changes occur in cardiac function in patients with hypo- or hyperthyroidism. T(3)-induced changes in cardiac function can result from direct or indirect T(3) effects. Direct effects result from T(3) action in the heart itself and are mediated by nuclear or extranuclear mechanisms. Extranuclear T(3) effects, which occur independent of nuclear T(3) receptor binding and increases in protein synthesis, influence primarily the transport of amino acids, sugars, and calcium across the cell membrane. Nuclear T(3) effects are mediated by the binding of T(3) to specific nuclear receptor proteins, which results in increased transcription of T(3)-responsive cardiac genes. The T(3) receptor is a member of the ligand-activated transcription factor family and is encoded by cellular erythroblastosis A (c-erb A) genes. T(3) also leads to an increase in the speed of diastolic relaxation, which is caused by the more efficient pumping of the calcium ATPase of the sarcoplasmic reticulum. This T(3) effect results from T(3)-induced increases in the level of the mRNA coding for the sarcoplasmic reticulum calcium ATPase protein, leading to an increased number of calcium ATPase pump units in the sarcoplasmic reticulum.
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            Mitochondrial transcription factor A (TFAM): roles in maintenance of mtDNA and cellular functions.

            A growing body of evidence suggests that mammalian mitochondrial DNA takes on higher structure called nucleoid or mitochromosome corresponding to that of nuclear DNA. Mitochondrial transcription factor A (TFAM), which was cloned as a transcription factor for mitochondrial DNA, has known to be essential for the maintenance of mitochondrial DNA. Human TFAM has an ability to bind to DNA in a sequence-independent manner and is abundant enough to cover whole region of mitochondrial DNA, owing to which TFAM stabilizes mitochondrial DNA through formation of nucleoid and regulates (or titrates) the amount of mitochondrial DNA. Overexpression of human TFAM in mice increases the amount of mitochondrial DNA and dramatically ameliorates the cardiac dysfunctions caused by myocardial infarction. The maintenance of integrity of mitochondrial DNA is important for keeping proper cellular functions both under physiological and pathological conditions. TFAM may play a crucial role in maintaining mitochondrial DNA as a main component of the nucleoid.
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              Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning.

              Ischemic preconditioning provides strong cardioprotection from ischemia, but its molecular mechanisms remain unknown. Convincing evidence confirms a central role of hypoxia-inducible factor (HIF)-1 in mammalian oxygen homeostasis. Thus, we pursued HIF-1 as a central component of cardioprotection by ischemic preconditioning. Murine studies of in situ preconditioning revealed a robust activation of cardiac HIF-1. Moreover, in vivo small interfering RNA repression of cardiac HIF-1 resulted in abolished cardioprotection by ischemic preconditioning. In contrast, pretreatment with the HIF activator dimethyloxalylglycine was associated with cardioprotection similar to that of ischemic preconditioning itself. Finally, selective small interfering RNA repression of prolylhydroxylase 2 resulted in significant activation of HIF-1 alpha and attenuated myocardial infarct sizes (0.44+/-0.09-fold). As an end point of HIF-dependent cardioprotection, we defined the role of A2B adenosine receptor (A2BAR) signaling. Although the cardiac A2BAR was induced with HIF activation, HIF-dependent cardioprotection was abolished in A2BAR-/- mice. Taken together, these studies provide evidence for a critical role of HIF-1 in ischemic preconditioning via enhancing purinergic signaling pathways.
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                Author and article information

                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                jcmm
                Journal of Cellular and Molecular Medicine
                Blackwell Publishing Ltd (Oxford, UK )
                1582-1838
                1582-4934
                March 2011
                20 January 2010
                : 15
                : 3
                : 514-524
                Affiliations
                [a ]Institute of Clinical Physiology CNR, Pisa, Italy
                [b ]Sector of Medicine Scuola Superiore Sant’Anna, Pisa, Italy
                [c ]Division of Cardiology, Feinberg Cardiovascular Institute, Northwestern University Chicago, IL, USA
                [d ]Division of Surgical, Molecular and Ultrastructural Pathology, Pisa University Hospital Pisa, Italy
                [e ]Department of Internal Medicine, University of Pisa and Pisa University Hospital Pisa, Italy
                [f ]Department of Physiology, New York Medical College Valhalla, NY, USA
                Author notes
                Correspondence to: Giorgio IERVASI, M.D., Institute of Clinical Physiology, CNR via G. Moruzzi n. 1, 56122 Pisa, Italy. Tel.: +39-050-3152016 Fax: +39-050-3152651 E-mail: iervasi@ 123456ifc.cnr.it

                These authors have contributed equally to the work.

                Article
                10.1111/j.1582-4934.2010.01014.x
                3922373
                20100314
                908b4c01-9827-4f60-ab36-be75467f6c71
                © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
                History
                : 03 November 2009
                : 30 December 2009
                Categories
                Articles

                Molecular medicine
                myocardial infarction,l-triiodothyronine,remodelling,mitokatp,angiogenesis
                Molecular medicine
                myocardial infarction, l-triiodothyronine, remodelling, mitokatp, angiogenesis

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