Immediate response of myocardium to pressure overload includes transient regulation of genes associated with mitochondrial bioenergetics and calcium availability (original) (raw)
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Proceedings of the National Academy of Sciences, 1989
The sarcoplasmic reticulum (SR) and the contractile protein myosin play an important role in myocardial performance. Both of these systems exhibit plasticity--i.e., quantitative and/or qualitative reorganization during development and in response to stress. Recent studies indicate that SR Ca2+ uptake function is altered in adaptive cardiac hypertrophy and failure. The molecular basis (genetic and phenotypic) for these changes is not understood. In an effort to determine the underlying causes of these changes, we characterized the rabbit cardiac Ca2+-ATPase phenotype by molecular cloning and ribonuclease A mapping analysis. Our results show that the heart muscle expresses only the slow-twitch SR Ca2+-ATPase isoform. Second, we quantitated the steady-state mRNA levels of two major SR Ca2+ regulatory proteins, the Ca2+-ATPase and phospholamban, to see whether changes in mRNA content might provide insight into the basis for functional modification in the SR of hypertrophied hearts. In r...
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.
AJP: Heart and Circulatory Physiology, 2013
Right ventricular (RV) and left ventricular (LV) myocardium differ in their pathophysiological response to pressure-overload hypertrophy. In this report we use microarray and proteomic analyses to identify pathways modulated by LV-aortic banding (AOB) and RV-pulmonary artery banding (PAB) in the immature heart. Newborn New Zealand White rabbits underwent banding of the descending thoracic aorta [LV-AOB; n = 6]. RV-PAB was achieved by banding the pulmonary artery ( n = 6). Controls ( n = 6 each) were sham-manipulated. After 4 (LV-AOB) and 6 (RV-PAB) wk recovery, the hearts were removed and matched RNA and proteins samples were isolated for microarray and proteomic analysis. Microarray and proteomic data demonstrate that in LV-AOB there is increased transcript expression levels for oxidative phosphorylation, mitochondria energy pathways, actin, ILK, hypoxia, calcium, and protein kinase-A signaling and increased protein expression levels of proteins for cellular macromolecular complex ...
Journal of Molecular and Cellular Cardiology, 2019
Here we aimed at investigating the relation between left ventricular (LV) contractility and myofilament function during the development and progression of pressure overload (PO)-induced LV myocardial hypertrophy (LVH). Methods: Abdominal aortic banding (AB) was performed to induce PO in rats for 6, 12 and 18 weeks. Sham operated animals served as controls. Structural and molecular alterations were investigated by serial echocardiography, histology, quantitative real-time PCR and western blot. LV function was assessed by pressurevolume analysis. Force measurement was carried out in permeabilized cardiomyocytes. Results: AB resulted in the development of pathological LVH as indicated by increased heart weight-to-tibial length ratio, LV mass index, cardiomyocyte diameter and fetal gene expression. These alterations were already present at early stage of LVH (AB-week6). Furthermore, at more advanced stages (AB-week12, AB-week18), myocardial fibrosis and chamber dilatation were also observed. From a hemodynamic point of view, the AB-wk6 group was associated with increased LV contractility, maintained ventriculo-arterial coupling (VAC) and preserved systolic function. In the same experimental group, increased myofilament Ca 2+ sensitivity (pCa 50) and hyperphosphorylation of cardiac troponin-I (cTnI) at Threonine-144 was detected. In contrast, in the AB-wk12 and AB-wk18 groups, the initial augmentation of LV contractility, as well as the increased myofilament Ca 2+ sensitivity and cTnI (Threonine-144) hyperphosphorylation diminished, leading to impaired VAC and reduced systolic performance. Strong correlation was found between LV contractility parameters and myofilament Ca 2+sensitivity among the study groups. Conclusion: Changes in myofilament Ca 2+ sensitivity might underlie the alterations in LV contractility during the development and progression of PO-induced LVH.
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
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...
Journal of Molecular and Cellular Cardiology, 2008
During pressure overload hypertrophy, selective changes in cardiac gene expression occur that regulate growth and modify the structural and functional properties of the myocardium. To determine the role of translational mechanisms, a murine model of transverse aortic constriction was used to screen a set of specified mRNAs for changes in translational activity by measuring incorporation into polysomes in response to acute pressure overload. Candidate mRNAs were selected on the basis of two main criteria: (1) the 5′-untranslated region of the mRNA contains an excessive amount of secondary structure (ΔG b −50 kCal/mol), which is postulated to regulate efficiency of translation, and (2) the protein product has been implicated in the regulation of cardiac hypertrophy. After 24 h of transverse aortic constriction, homogenates derived from the left ventricle were layered onto 15-50% linear sucrose gradients and resolved into monosome fractions (messenger ribonucleoprotein particles) and polysome fractions by density gradient ultracentrifugation. The levels of mRNA in each fraction were quantified by real-time RT-PCR. The screen revealed that pressure overload increased translational activity of 6 candidate mRNAs as determined by a significant increase in the percentage of total mRNA incorporated into the polysome fractions. The mRNAs code for several functional classes of proteins linked to cardiac hypertrophy: the transcription factors c-myc, c-jun and MEF2D, growth factors VEGF and FGF-2 and the E3 ubiquitin ligase MDM2. These studies demonstrate that acute pressure overload alters cardiac gene expression by mechanisms that selectively regulate translational activity of specific mRNAs.
AJP: Heart and Circulatory Physiology, 2006
Early cardiovascular changes evoked by pressure overload (PO) may reveal adaptive strategies that allow immediate survival to the increased hemodynamic load. In this study, systolic and diastolic Ca2+ cycling was analyzed in left ventricular rat myocytes before ( day 2, PO-2d group) and after ( day 7, PO-7d group) development of hypertrophy subsequent to aortic constriction, as well as in myocytes from time-matched sham-operated rats (sham group). Ca2+ transient amplitude was significantly augmented in the PO-2d group. In the PO-7d group, intracellular Ca2+ concentration ([Ca2+]i) was reduced during diastole, and mechanical twitch relaxation (but not [Ca2+]i decline) was slowed. In PO groups, fractional sarcoplasmic reticulum (SR) Ca2+ release at a twitch, SR Ca2+ content, SR Ca2+ loss during diastole, and SR-dependent integrated Ca2+ flux during twitch relaxation were significantly greater than in sham-operated groups, whereas the relaxation-associated Ca2+ flux carried by the Na+/...
Journal of Molecular and Cellular Cardiology, 2007
In many forms of congenital heart disease, the right ventricle (RV) is subject to abnormal loading conditions resulting in RV hypertrophy and remodeling. We determined the alterations in RV cytoplasmic proteomic phenotype that occur during prolonged periods of RV pressure overload. We performed a differential proteomic profiling study on RV hypertrophy using an animal model of various durations of pulmonary artery banding (PAB) in parallel with hemodynamic characterization. This hemodynamic evaluation showed that after 6, 12 and 20 weeks of PAB, the RV is in a compensated state of hypertrophy. Overall, the majority of protein changes were metabolism related indicating a shift towards the glycolytic pathway at the expense of β-oxidation in the RV of the PAB animals. The changes in proteins related to the glycolytic pathway, exemplified by enolase and creatine kinase B-chain, tended to precede changes in β-oxidation. In parallel, increases in stress chaperones, exemplified by several phosphorylated HSP-27 species, are present from the 6 week time point, whereas increases in antioxidant proteins, exemplified by peroxiredoxin 2 and 6, appear to be restricted to the 12 week time point. The p38 MAPK signal transduction pathway appears not to be activated. Observed protein changes are likely part of a protective mechanism against the development of RV failure.