Heart failure often complicates myocardial infarction (MI), and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA2a) is underexpressed in the failing myocardium. We examined the effect of ...preexisting cardiac SERCA2a protein overexpression on rat survival and left ventricular (LV) remodeling after MI.
Baseline myocardial SERCA2a expression was 37% higher in transgenic (TG) rats than in their wild-type (WT) controls, consistent with enhanced myocardial function. The mortality rate of TG rats during the 24 hours after surgical MI was higher than that of WT rats (71% versus 35%, P<0.001), associated with a higher frequency of ventricular arrhythmias, and was normalized by lidocaine treatment. The increased acute-phase mortality in TG rats was not accompanied by increased 6-month mortality. Function of the noninfarcted myocardium, as assessed by tissue Doppler imaging, was higher in TG rats than in WT rats for up to 1 month after MI, a beneficial effect no longer observed at 3 months. LV remodeling and global function were similar in TG and WT rats. No difference in papillary muscle function was found at 6 months.
Constitutive cardiac SERCA2a overexpression has a transient beneficial effect on remote myocardium function in rat MI, with no improvement in LV global function or prevention of LV remodeling and failure. This benefit is associated with a higher risk of acute mortality, which is prevented by lidocaine treatment.
Background: The cardiovascular system and central nervous system are known to influence each other. Accordingly, neurological changes may occur after myocardial infarction (MI), which may be mediated ...by neuroinflammation. We investigated tumor necrosis factor alpha (TNF-α) and microglia activation in post-MI neuroinflammation. Materials and Methods: MI or sham surgery was induced in 28 male mice. Two weeks later, we performed echocardiography and dissected the brains for the western blot on TNF-α and its receptors (n = 10) or immunohistochemical stainings for microglia, doublecortin X (DCX), and TNF-α (n = 18). Plasma was collected for the measurement of circulatory cytokines. Results: The MI mice had an average infarct size of 38% of the left ventricle, heart failure was confirmed by decreased fractional shortening and increased lung weight. Plasma cytokine levels were unaltered. In brains of MI mice, there was a higher expression of TNF-α precursor protein, with trends for higher TNF-R1 and lower TNF-R2 expression. Furthermore, MI mice had more activated microglia in the inner blade of the dentate gyrus of the hippocampus. The amount of neurogenesis measured by DCX staining was unaltered. Conclusions: Our mouse model of MI showed signs of persistent neuroinflammation as indicated by raised levels of TNF-α precursor protein and an increased number of activated microglia in the hippocampus. The extent to which these neuroinflammatory hallmarks influence central nervous system functioning remain to be determined.
H9c2 cardiomyoblasts produce thyroid hormone Meischl, Christof; Buermans, Henk P; Hazes, Thierry ...
American Journal of Physiology: Cell Physiology
294, Številka:
5
Journal Article
Recenzirano
Thyroid hormone acts on a wide range of tissues. In the cardiovascular system, thyroid hormone is an important regulator of cardiac function and cardiovascular hemodynamics. Although some early ...reports in the literature suggested an unknown extrathyroidal source of thyroid hormone, it is currently thought to be produced exclusively in the thyroid gland, a highly specialized organ with the sole function of generating, storing, and secreting thyroid hormone. Whereas most of the proteins necessary for thyroid hormone synthesis are thought to be expressed exclusively in the thyroid gland, we now have found evidence that all of these proteins, i.e., thyroglobulin, DUOX1, DUOX2, the sodium-iodide symporter, pendrin, thyroid peroxidase, and thyroid-stimulating hormone receptor, are also expressed in cardiomyocytes. Furthermore, we found thyroglobulin to be transiently upregulated in an in vitro model of ischemia. When performing these experiments in the presence of 125 I, we found that 125 I was integrated into thyroglobulin and that under ischemia-like conditions the radioactive signal in thyroglobulin was reduced. Concomitantly we observed an increase of intracellularly produced, 125 I-labeled thyroid hormone. In conclusion, our findings demonstrate for the first time that cardiomyocytes produce thyroid hormone in a manner adapted to the cell's environment.
In neonatal ventricular cardiomyocytes (NVCM), decreased contractile activity stimulates sarco-endoplasmic reticulum Ca
2+
-ATPase2a (SERCA2a), analogous to reduced myocardial load in vivo. This ...study investigated in contracting NVCM the role of load-dependent RhoA-ROCK signaling in SERCA2a regulation. Contractile arrest of NVCM resulted in low peri-nuclear localized RhoA levels relative to contracting NVCM. In arrested NVCM, ROCK activity was decreased (59%) and paralleled a loss in F-actin levels. Y-27632-induced ROCK inhibition in contracting NVCM increased SERCA2a messenger RNA expression by 150%. This stimulation was transcriptional, as evident from transfections with the SERCA2a promoter. A reciprocal effect of Y-27632 treatment on the promoter activity of atrial natriuretic factor was observed. SERCA2a transcription was not altered by co-transfection of the RhoA-ROCK-dependent serum response factor (SRF) alone or in combination with myocardin. Furthermore, GATA4, another ROCK-dependent transcription factor, induced rather than repressed SERCA2a transcription. This study shows that contractile activity suppresses SERCA2a gene expression via RhoA-ROCK-dependent transcription modulation. This modulation is likely to be accomplished by a transcription factor other than SRF, myocardin, or GATA4.
The iodothyronine deiodinases initiate or terminate thyroid hormone action and therefore are critical for the biological effects mediated by thyroid hormone. Over the years, research has focused on ...their role in preserving serum levels of the biologically active molecule T3 during iodine deficiency. More recently, a fascinating new role of these enzymes has been unveiled. The activating deiodinase (D2) and the inactivating deiodinase (D3) can locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of changes in thyroid hormone serum concentrations. This mechanism is particularly relevant because deiodinase expression can be modulated by a wide variety of endogenous signaling molecules such as sonic hedgehog, nuclear factor-κB, growth factors, bile acids, hypoxia-inducible factor-1α, as well as a growing number of xenobiotic substances. In light of these findings, it seems clear that deiodinases play a much broader role than once thought, with great ramifications for the control of thyroid hormone signaling during vertebrate development and metamorphosis, as well as injury response, tissue repair, hypothalamic function, and energy homeostasis in adults.
Downregulation of sarco-endoplasmic reticulum calcium ATPase 2a (SERCA2a) expression is a critical marker of pathological myocardial hypertrophy. The effects of calcium-dependent signaling and of ...contractile activity on the regulation of myocardial SERCA2a expression remain unclear. The present study dissociates effects of calcium-dependent signaling through calcineurin (CN) and calmodulin dependent protein kinase-II (CAMK-II), from effects of contractile activity in spontaneously contracting rat neonatal ventricular cardiomyocytes (NVCM) using 2,3-butanedione monoxime (BDM), which arrests contractions but maintains calcium fluxes.
SERCA2a mRNA expression was analysed using Northern hybridisation in spontaneously contracting NVCM (control) and in NVCM treated with either BDM, L-type Ca2+-channel blocker (verapamil), CN-blocker (cyclosporin A; CsA), CAMK-II blocker (KN-93), or combinations thereof. Transient transfection of the CN-dependent transcription factor nuclear factor of activated T-lymphocytes (NFATc), coupled to GFP, was used to detect NFAT nuclear translocation. The effects of CN/CAMK-II-dependent signaling were further dissected into effects of the transcription factors NFATc4 and myocyte enhancer factor 2c (MEF2c) on the activity of various SERCA2a promoter fragments using transient transfection assays.
Treatment with BDM induced a 2.5-fold rise in SERCA2a mRNA, which was abolished by addition of verapamil and was reduced by addition of CsA (-40%) and KN-93 (-20%). NFAT nuclear translocation was similar in control and BDM-treated NVCM. SERCA2a promoter activity was stimulated by NFATc4 and MEF2c, but only when both factors were co-transfected.
Following contractile arrest with BDM, upregulation of SERCA2a mRNA expression by CN/CAMK-II signaling becomes evident. This upregulation is likely the result of synergistic stimulation of SERCA2a promoter activity by NFATc4 and MEF2c. Contractile activity opposes this upregulation through distinct and independent pathways.
Chronic low-frequency contraction of skeletal muscle, either induced by a slow motor nerve or through direct electrical stimulation, generally induces expression of proteins associated with the slow ...phenotype, while repressing the corresponding fast isoforms. Contractions thereby counteract the primarily transcriptional effect of thyroid hormone (T3) which results in the selective induction and stimulation of expression of fast isoforms. We studied the regulation of expression of the fast-type sarcoplasmic-reticulum Ca2+-ATPase (SERCA1), a characteristic component of the fast phenotype. Previous work suggested that reduction of SERCA1 expression by contractile activity might result from interference with the T3-dependent transcriptional stimulation of the SERCA1 gene. The present study was set up to test this unexpected mode of action of contractile activity. We show that electrical stimulation of C2C12 mouse myotubes, which results in synchronous contractions at the imposed frequency, reduces basal but virtually abolishes T3-dependent SERCA1 expression. T3-dependent expression of a reporter gene driven by the SERCA1 promoter was similarly affected by electrical stimulation. This is the first demonstration that the counteracting effects on muscle gene expression of electrically induced contractions and T3 may interact at the transcriptional level.
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