Regulation of myocardial Ca2+-ATPase and phospholamban mRNA expression in response to pressure overload and thyroid hormone (original) (raw)
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Circulation Research, 1990
The reduction in Ca2+ concentration during diastole and relaxation occurs differently in normal hearts and in hypertrophied hearts secondary to pressure overload. We have studied some possible molecular mechanisms underlying these differences by examining the function of the sarcoplasmic reticulum and the expression of the gene encoding its Ca2(+)-ATPase in rat hearts with mild and severe compensatory hypertrophy induced by abdominal aortic constriction. Twelve sham-operated rats and 31 operated rats were studied 1 month after surgery. Eighteen animals exhibited mild hypertrophy (left ventricular wt/body wt less than 2.6) and 13 animals severe hypertrophy (left ventricular wt/body wt greater than 2.6). During hypertrophy we observed a decline in the function of the sarcoplasmic reticulum as assessed by the oxalate-stimulated Ca2+ uptake of homogenates of the left ventricle. Values decreased from 12.1 +/- 1.2 nmol Ca2+/mg protein/min in sham-operated rats to 9.1 +/- 1.5 and 6.7 +/- 1...
Genetics and Molecular Biology, 2010
Ventricular hypertrophy is one of the major myocardial responses to pressure overload (PO). Most studies on early myocardial response focus on the days or even weeks after induction of hypertrophic stimuli. Since mechanotransduction pathways are immediately activated in hearts undergoing increased work load, it is reasonable to infer that the myocardial gene program may be regulated in the first few hours. In the present study, we monitored the expression of some genes previously described in the context of myocardial hypertrophic growth by using the Northern blot technique, to estimate the mRNA content of selected genes in rat myocardium for the periods 1, 3, 6, 12 and 48 h after PO stimuli. Results revealed an immediate switch in the expression of genes encoding alpha and beta isoforms of myosin heavy chain, and up-regulation of the cardiac isoform of alpha actin. We also detected transitory gene regulation as the increase in mitochondrial cytochrome c oxidase 1 gene expression, parallel to down-regulation of genes encoding sarco(endo)plasmic reticulum Ca +2 ATPase and sodium-calcium exchanger. Taken together, these results indicate that initial myocardial responses to increased work load include alterations in the contractile properties of sarcomeres and transitory adjustment of mitochondrial bioenergetics and calcium availability.
Japanese Circulation Journal, 2001
The cellular mechanisms of abnormal calcium regulation and excitation -contraction coupling in relation to glucose metabolism in the hypertrophied heart are not well understood. The present study evaluated the myocardial mechanics of 6-7-week-old pressure overload hypertrophied rabbit hearts in response to dobutamine by (1) serial echocardiograms in vivo and (2) isolated Langendorff perfusion. Cytosolic Ca 2+ ([Ca 2+ ]i) and sarcoplasmic reticulum Ca 2+ -ATPase (SERCA2) expression were measured by fluorescence spectroscopy and Western immunoblotting, respectively. The effect of glycolytic inhibition by 2-deoxy-D-glucose ± pyruvate was also evaluated. Both systolic and diastolic [Ca 2+ ]i tended to be higher and diastolic calcium removal ( Ca) significantly slower in the hypertrophied heart. The myocardial response to dobutamine was blunted and dobutamine insignificantly improved Ca. The SERCA2 protein level was higher in early hypertrophy, but was significantly reduced by 6 weeks of age, with progressive contractile failure. Inhibition of glycolysis or SERCA2 caused an increase in [Ca 2+ ]i as well as a slower Ca. Pyruvate completely preserved myocardial function and [Ca 2+ ]i handling during glycolytic inhibition. It was concluded that in this model of advanced pressure overload hypertrophy, contractile failure and inotrope insensitivity are associated with increased [Ca 2+ ]i, slower Ca and reduced sensitivity of the contractile proteins to Ca 2+ . These changes occur in association with downregulation of the SERCA2, probably caused by impaired glucose metabolism. (Jpn Circ J 2001; 65: 1064 -1070
Basic Research in Cardiology, 1999
It is unknown whether the transmural heterogeneity of sarcoplasmic reticulum (SR) Ca 2+-ATPase gene expression is present within the left ventricular (LV) wall. Moreover, the changes of transmural distribution have not been examined in the failing hearts. We thus quantified steady-state mRNA abundance of SR Ca 2+ regulatory proteins by Northern blot analysis in both subendocardial and subepicardial LV layers from normal and rapid pacing-induced heart failure (HF) dog hearts. For normal LV, Ca 2+-ATPase mRNA abundance (normalized to glyceraldehyde-3-phosphate dehydrogenase [GAPDH] mRNA) was significantly reduced in the subendocardium, whereas calsequestrin mRNA abundance was comparable between the two layers. For HF LV, Ca 2+-ATPase mRNA abundance in the subendocardium was also reduced compared to the subepicardium. However, the endocardium to epicardium ratio was comparable between control and HF (0.62 ± 0.08 vs. 0.65 ± 0.07; p = NS). Therefore, the transmural gradient of this gene was constant in both control and HF. Even though the data on the transmural heterogeneity of protein level is not available, the subendocardium contained significantly less Ca 2+-ATPase mRNA, which might contribute, at least in part, to the transmural gradients of biochemical and mechanical function.
Journal of Clinical Investigation, 1990
A decrease in the myocardial level of the mRNA encoding the Ca2+-ATPase of the sarcoplasmic reticulum (SR) has been recently reported during experimental cardiac hypertrophy and failure. To determine if such a deficit occurs in human endstage heart failure, we compared the SR Ca2+-ATPase mRNA levels in left (LV) and right ventricular (RV) specimens from 13 patients undergoing cardiac transplantation (6 idiopathic dilated cardiomyopathies; 4 coronary artery diseases with myocardial infarctions; 3 diverse etiologies) with control heart samples using a rat cardiac SR Ca2+-ATPase cDNA probe. We observed a marked decrease in the mRNA for the Ca2+-ATPase relative to both the 18S ribosomal RNA and the myosin heavy chain mRNA in LV specimens of patients with heart failure compared to controls (-48%, P < 0.01 and -47%, P < 0.05, respectively). The LV ratio of Ca2+-ATPase mRNA to 18S RNA positively correlated with cardiac index (P < 0.02).
Subcellular Remodeling and Heart Dysfunction in Cardiac Hypertrophy due to Pressure Overloada
Annals of the New York Academy of Sciences, 1999
Rats were treated with etomoxir, an inhibitor of palmitoyltransferase-1, to examine the role of a shift in myocardial metabolism in cardiac hypertrophy. Pressure overload was induced by abdominal aorta banding for 8 weeks. Sham-operated animals served as control. Left ventricular dysfunction, as reflected by decreased LVDP, +dP/dt, −dP/dt, and elevated LVEDP in the pressure overloaded animals, was improved by treatment with etomoxir. Cardiac hypertrophy in pressure-overload rats decreased the sarcoplasmic reticular (SR) Ca 2+ uptake and Ca 2+ release as well as myofibrillar Ca 2+-stimulated ATPase and myosin Ca 2+-ATPase activities; these changes were attenuated by treatment with etomoxir. Steady-state mRNA levels for =and >-myosin heavy chains, SR Ca 2+-pump, and protein content of SR Ca 2+-pump were reduced in hypertrophied hearts; these alterations were prevented by etomoxir treatment. The results indicate that modification of changes in myocardial metabolism by etomoxir may prevent remodeling of myofibrils and SR membrane and thereby improve cardiac function in hypertrophied heart.
Cardiovascular Research, 1999
See article by Bluhm et al. [18] (pages 382-388) in this hypertrophy has led to the proposal that hypertrophy itself issue. may recapitulate ontogeny [13-15]. Therefore, the heart failure process that occurs in the context of myocardial Recent advances in animal genetics and transgenic hypertrophy or complex metabolic disorders that impact technology have blossomed into one of the dominant the cardiovascular system is closely entangled with the strategies to explore the consequences of gene defects in impairment of the myocyte program of growth and difdifferent organ systems in the in vivo context. Such a ferentiation. These considerations pose the problem of perspective has been progressively applied to the car-identifying endogenous molecules that can restore the diovascular system to dissect complex in vivo physiologic myocardial contractility in the course of diseases bearing a and pathologic states. The encouraging results achieved so complex genetic background, including different types of far in the field of heart hypertrophy and failure with the aid acquired or genetically determined myocardial hyperof engineered mouse models have even suggested consid-trophy, hereditary cardiomyopathies, and cardiomyopathic eration for the cardiovascular system as a paradigm for processes associated with diabetes or hypothyroidism. The