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Biomedical subjects

A M Samarel

Publications and source records attributed to A M Samarel.

At least 55 records · Page 3Linked to original sources
PubMed1994

Regulation of rat ventricular myosin heavy chain expression by serum and contractile activity.

To quantitatively analyze the effects of serum stimulation and contractile activity and their interaction on cellular growth and cardiac myosin heavy chain (MHC) gene expression, spontaneously contracting neonatal rat ventricular myocytes in primary culture were maintained in serum-free growth medium or growth medium supplemented with fetal bovine serum. Contractile activity in paired cultures was inhibited by addition of the calcium channel blocker verapamil (10 microM) to the culture medium. Both serum stimulation and contractile activity produced myocyte hypertrophy as assessed by increases in total protein, total RNA, protein-to-DNA ratios, and total MHC protein content. MHC isoenzyme analysis indicated that both MHC-alpha and MHC-beta proteins accumulated in response to serum stimulation and/or contractile activity. The increases in MHC-beta protein resulting from serum stimulation and contractile activity occurred in parallel with increases in MHC-beta mRNA. In contrast, MHC-alpha mRNA levels were relatively unaffected by serum stimulation but appeared to decrease in response to contractile activity. The protein kinase inhibitor staurosporine (5 nM) reduced MHC-beta expression in serum-free, contracting cultures and also prevented the serum-induced increase in MHC-beta mRNA observed in both contracting and arrested myocytes. Staurosporine also increased MHC-alpha mRNA levels in serum-free, contracting, and verapamil-arrested myocytes. These data suggest that both humoral and mechanical factors regulate MHC isoenzyme expression and cellular growth in neonatal ventricular myocytes.

Alkaloids↗
PubMed1994

Contractile arrest increases sarcoplasmic reticulum calcium uptake and SERCA2 gene expression in cultured neonatal rat heart cells.

We developed protocols with intact cultured neonatal rat myocytes to directly evaluate the function of the sarcoplasmic reticulum (SR) Ca-ATPase (or SERCA2), Na-Ca exchange (Na-CaX), and slow Ca transport systems (mitochondria and sarcolemmal Ca-ATPase). Spontaneously beating control cells were compared with cells cultured for 2 days in the presence of verapamil (verapamil-arrested cells, VA). Intracellular calcium (Cai) transients were measured by use of indo-1 during (1) spontaneous twitches, (2) contractures induced by rapid application of caffeine (CafC, with and without Nao), and (3) twitches induced by brief depolarizations with high [K]o solution (K-twitches). We also measured mRNA levels for the SR Ca-ATPase and Na-CaX in the same experimental preparations. The t1/2 for [Ca]i decline when both the SR Ca uptake and Na-CaX were prevented was the same for control and VA cells (approximately 20 seconds), indicating unaltered slow Ca transport systems. Similarly, there was no significant difference in the t1/2 of CafC when Na-CaX was the main mechanism responsible for [Ca]i decline (t1/2 approximately 1.5 seconds), indicating unaltered Na-CaX. Conversely, we found nearly a twofold increase in the rate of [Ca]i decline during K-twitches (control t1/2, 0.84 +/- 0.05 seconds; VA t1/2, 0.48 +/- 0.06 second; P < .001), indicating an increase in SR Ca-pumping activity in VA cells. This was also reflected by a 56% increase in the peak [Ca]i reached during CafC used to assess maximal SR Ca content (427 +/- 49 nmol/L in control versus 665 +/- 75 nmol/L in VA cells).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Formation of fetal rat cardiac cell clones by retroviral transformation: retention of select myocyte characteristics.

Ventricular myocyte (cardiomyocyte) growth is exquisitely regulated such that embryonic and fetal development are the primary periods of active cellular division. This report describes formation of three separate cardiomyocyte cell clones obtained by replication-defective retroviral (v/myc and v-H-ras) transformation of primary cultures of day-16 fetal rat cardiomyocytes. The cell clones do not spontaneously contract, yet they express several cardiac-specific (cardiac troponin-C, alpha-cardiac actin) and associated genes (Connexin 43, Early growth response gene-1) with stable expression of several genes determined through the 28th passage. None of these cell clones express skeletal muscle actin or the skeletal muscle regulatory gene MyoD1; yet all display ultrastructural and biochemical evidence of their cardiac muscle lineage. Molecular and biochemical studies of cardiac-specific gene regulation can be anticipated from the cell clones as it pertains to nuclear transcription factors and transient CAT-based reporter gene constructs. The formation of these cell clones will enable further studies of growth and development of this unique muscle cell population of the cardiovascular system to be performed at the cellular and molecular level.

Animals↗
PubMed1993

Catecholamines modulate protein turnover in cultured, quiescent rabbit cardiac myocytes.

When rabbit ventricular myocytes were cultured for 1 wk and then exposed to alpha- and/or beta-adrenergic agonists, such nonbeating heart cell preparations disclosed increased protein-to-DNA ratios and elevated RNA content, indicative of cellular hypertrophy. Norepinephrine, isoproterenol, and phenylephrine provoked hypertrophy with norepinephrine eliciting a greater response than isoproterenol or phenylephrine. Specific alpha- and beta-antagonists blocked growth by inhibiting catecholamine-induced changes in protein turnover. Each catecholamine enhanced the fractional rate of protein synthesis within 48 h; however, changes in growth rates appeared to be modulated, in part, by alterations in protein degradation. Even though rates of total protein and actin synthesis resembled values measured in vivo, myosin heavy chain fractional rate of synthesis was only 22% of in vivo levels. Double label immunofluorescence microscopy further illustrated that catecholamine treatment accelerated myofibrillar disruption in these quiescent heart cells. These observations suggested that in the absence of beating, neurohumoral modulation of contractile protein turnover was not associated with the maintenance of myofibrillar integrity even though catecholamines induced cellular hypertrophy.

Animals↗
PubMed1993

Cyclosporine A has no direct effect on collagen metabolism by cardiac fibroblasts in vitro.

BACKGROUND: Cyclosporine A has been implicated in the pathogenesis of myocardial interstitial fibrosis observed in heart transplant recipients. However, other confounding variables such as posttransplantation hypertension and rejection episodes may also be responsible for interstitial fibrosis development and associated abnormalities in ventricular diastolic function. Therefore, we examined whether cyclosporine A directly or indirectly affects fibrillar collagen metabolism by cardiac fibroblasts in vitro. METHODS AND RESULTS: Rat cardiac fibroblasts were isolated by collagenase digestion. Subconfluent cultures were then maintained (24 hours) in serum-containing or serum-free medium before addition of cyclosporine A (50-1,000 ng/mL). After an additional 24 hours, total procollagen synthesis, accumulation, and degradation were analyzed by measuring hydroxyproline content in the cell monolayer and in the ethanol-soluble and ethanol-precipitable fractions of the culture medium. mRNA levels for alpha 1(I) and alpha 1(III) procollagen polypeptides were assessed 2, 6, 12, and 24 hours after cyclosporine A treatment using Northern blot analysis. The results were compared with control cultures maintained in the absence of cyclosporine A. There were no differences in procollagen gene expression, total procollagen synthesis, accumulation, or degradation in cardiac fibroblasts treated directly with cyclosporine A, in concentrations up to 1,000 ng/mL, compared with untreated cells. In additional experiments, we examined whether cyclosporine A might stimulate the production of collagen regulatory substances by cardiac myocytes in culture. However, addition of conditioned media from neonatal myocytes maintained in the presence and absence of cyclosporine A (1,000 ng/mL) also had no effect on collagen deposition by cardiac fibroblasts. CONCLUSIONS: We conclude that cyclosporine A has no direct effect on collagen metabolism by cultured cardiac fibroblasts in vitro. In addition, we have excluded a paracrine effect of ventricular myocytes on collagen production in the presence of cyclosporine A. These results suggest that factors other than cyclosporine A are responsible for the interstitial fibrosis observed in cardiac allografts.

Animals↗
PubMed1993

Contractile activity modulates actin synthesis and turnover in cultured neonatal rat heart cells.

In this study, the role that active tension development plays in the formation and maintenance of cardiac myocyte myofibrillar structure and cellular shape was investigated. By use of the calcium channel blocker verapamil, spontaneous contractile activity of neonatal rat heart myocytes was inhibited for 24 to 96 hours. Confocal microscopy of rhodamine phalloidin-stained cells revealed that, within 24 hours of contractile arrest, actin filaments of myofibrils were no longer aligned with one another at their I bands and Z lines. Cellular shape was also affected, with the cells developing a less stellate appearance while remaining attached to the substrate as well as to one another. By 48 hours, actin fibrils were largely absent from these cells. The disappearance of actin was confirmed by measurements of actin synthesis and accumulation rates and by pulse-chase biosynthetic labeling experiments. It was revealed that, although actin synthesis was significantly reduced in arrested myocytes, the rapid disappearance of total cellular actin was largely due to increased rates of actin degradation. Contractile arrest produced by L-type calcium channel blockade with verapamil (or other calcium channel blockers) accelerated actin degradation to a greater extent than K+ depolarization. Chloroquine partially suppressed the accelerated rate of actin degradation, indicating that lysosomal proteolysis may be involved in actin degradative processing. Protein kinase C activation also partially inhibited the accelerated rate of actin degradation but did not restore actin filaments in arrested myocytes. The reformation of actin fibrils and their reassembly into striated myofibrils occurred when contractile activity was restored by removal of verapamil from the culture medium. The period of time required for myocytes to reassemble actin filaments and to regain their elongated morphology was proportional to the period of time that the cells were inhibited from contracting. Data are presented to indicate that active tension development by neonatal cardiac myocytes in culture is critical to the maintenance of filamentous actin structure via mechanisms involving actin assembly, disassembly, and degradation.

Actins↗
PubMed1993

Regulation of procollagen metabolism in the pressure-overloaded rat heart.

To determine the molecular events responsible for the disproportionate accumulation of myocardial fibrillar collagens during sustained hypertension, we examined the in vivo rate of procollagen synthesis, collagen accumulation, and intracellular procollagen degradation 1-16 wk after abdominal aortic banding in young rats. These measurements were correlated with tissue mRNA levels for type I and type III procollagen polypeptides. Banded animals developed moderate, sustained hypertension and mild left ventricular hypertrophy. Increased type III procollagen mRNA levels were detected early after banding and persisted for the entire observation period. Disproportionate collagen accumulation without histological evidence of fibrosis was noted within 1 wk after hypertension induction. Fibrillar collagen accumulation at this time point resulted not from a major increase in procollagen synthesis, but rather a marked decrease in the rate of intracellular procollagen degradation. Interstitial fibrosis, however, was observed 16 wk after banding. Type I procollagen mRNA levels were increased six-fold, but only after 16 wk of hypertension. These results correlated well with the results of in vivo procollagen synthesis experiments at 16 wk, which demonstrated a threefold increase in left ventricular procollagen biosynthesis. We conclude that pretranslational as well as posttranslational mechanisms regulate fibrillar collagen deposition in the myocardial extracellular matrix during sustained hypertension.

Animals↗
PubMed1992

Contractile arrest accelerates myosin heavy chain degradation in neonatal rat heart cells.

Mechanical forces influence the growth and metabolism of a variety of cells, including cultured neonatal rat ventricular myocytes. To determine whether mechanical activity affected the synthesis and turnover of myosin heavy chain (MHC) in these striated muscle cells, MHC fractional degradative rates were measured in spontaneously beating cells and in arrested myocytes in which contractile activity was prevented by L-channel blockade (with verapamil, nifedipine, nisoldipine, and diltiazem) or K+ depolarization. MHC degradative rates were measured as the difference between rates of MHC synthesis and accumulation and in pulse-chase biosynthetic labeling experiments. Both methods indicated that contractile arrest markedly increased MHC degradation. Contractile arrest produced by L-channel blockade accelerated MHC degradation to a greater extent than K+ depolarization. The signal transduction pathway linking contractile activity to alterations in MHC degradation did not involve protein kinase C (PKC), because MHC degradation was unaffected by activating PKC in arrested cells or inhibiting PKC in spontaneously beating cells. Chloroquine and E-64 did not suppress the accelerated MHC degradation, suggesting that the rate-limiting step in MHC turnover occurred before degradative processing by cellular proteinases. Using a computer simulation, we hypothesize that the rate-limiting step in MHC turnover preceded (or was coincident with) MHC release from thick filaments. Thus mechanical forces may influence MHC half-life by regulating the rate of myosin disassembly.

Animals↗
PubMed1992

Thyroid hormone effects on cardiac gene expression independent of cardiac growth and protein synthesis.

Prior studies have demonstrated the importance of hemodynamic loading in mediating thyroxine (T4)-induced cardiac hypertrophy. Direct cellular effects of thyroid hormone have been implicated in modulating the expression of the myosin heavy chain (MHC) genes and the slow sarcoplasmic reticulum calcium adenosine triphosphatase (SR Ca(2+)-ATPase) gene. In the present report, administration of T4 for 72 h did not stimulate growth of the hemodynamically unloaded heterotopic isograft. The synthetic rates of total cardiac proteins and MHC in the isograft remained significantly lower at 64 and 53% of the respective rates measured simultaneously in the in situ working heart. Although total left ventricle RNA content in the isograft was unchanged by T4, alpha-MHC and SR Ca(2+)-ATPase mRNA concentrations were increased 181 and 208%, respectively, and the previously observed beta-MHC expression was completely prevented. These data indicate that, although T4 requires an increased hemodynamic load to stimulate cardiac protein synthesis, it is capable of directly altering the expression of at least two myocyte-specific genes. Therefore some of the phenotypic alterations observed with thyroid hormone treatment are the result of direct effects of the hormones on specific cardiac genes and independent of changes in cardiac growth.

Animals↗
PubMed1992

Hemodynamic regulation of myosin heavy chain gene expression. Studies in the transplanted rat heart.

Cardiac work is a major determinant of heart size and growth. Heterotopic cardiac isografts are hemodynamically unloaded and undergo atrophy. To determine the molecular changes that occur as a result of hemodynamic unloading, we have studied the rate of synthesis of total cardiac proteins and myosin heavy chain (MHC) and the expression of the myosin heavy chain gene as reflected in the messenger RNA levels for alpha- and beta-MHC isoforms. 72 h after transplantation there is a significant decrease in left ventricular size accompanied by a 27% decrease in the rate of total cardiac protein synthesis and a 53% decrease in the rate of myosin heavy chain synthesis. In contrast to isografts 14 d after transplantation which have a decrease in protein synthetic capacity, simultaneous measurements of 18S ribosomal RNA and myosin messenger RNA suggest that after 3 d the decrease in synthesis is due to a change in the efficiency of protein translation. While the working in situ heart expresses primarily alpha-MHC mRNA (97%) hemodynamic unloading leads to a 43% decrease in alpha-MHC mRNA concentration and the de novo expression of the beta-MHC mRNA. Total MHC mRNA (alpha plus beta) concentration analyzed by a quantitative S1 nuclease protection assay was similar in the two groups of hearts. Thus, in association with hemodynamic unloading there are changes in cardiac myosin heavy chain content as a result of both gene transcription and protein translation mechanisms.

Animals↗
PubMed1991

Asparaginyl deamidation-methylation of rat ventricular myosin light chains.

Spontaneous asparaginyl deamidation can produce damage to cytoskeletal proteins, and may lead to their targeting for subsequent rapid intracellular breakdown or repair. To test if myofibrillar proteins are subject to spontaneous deamidation damage in vitro, purified rat ventricular myosin light chain 1 (MLC1v) and phosphorylatable myosin light chain 2 (MPLC2v) were incubated (37 degrees C, 4 h, pH 2-11), and tested as substrates for human erythrocyte and rat cardiac protein carboxyl methyltransferase (PCMT). PCMT catalyzes the transfer of a methyl group from [3H-methyl] S-adenosyl methionine to deamidated asparaginyl residues and altered aspartyl residues on damaged proteins. MLC1v and MPLC2v underwent extensive incubation damage at neutral and alkaline pH. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorography revealed 3H-incorporation into MLC1v, MPLC2v, and a Mr = 14,000 polypeptide. 3H-methylated, CNBr-cleavage fragments of PCMT-methylated light chains were then separated by reverse-phase high performance liquid chromatography, and sequenced by automated Edman degradation. The major 3H-labeled peptide of the Mr = 14,000 protein proved homologous to residues 84 to 104 of rat MPLC2v, with a proposed deamidation site at Asn99-Ala100. The major 3H-labeled peptide from MLC1v proved homologous to residues 73 to 111 of rat cardiac MLC1v, with a proposed deamidation site at Asn108-Ser109. These results indicate that both myofibrillar protein subunits undergo selective non-enzymatic degradation at neutral and alkaline pH, resulting in the formation of methyl acceptor sites for human erythrocyte and rat cardiac PCMT. PCMT-catalyzed methylation of ventricular myosin light chains may be important in the repair, or subsequent proteolysis of these long-lived structural proteins of the myofibril.

Animals↗
PubMed1991

In vivo measurements of protein turnover during muscle growth and atrophy.

To investigate the influence of alterations in protein synthetic and degradative rates to the regulation of muscle mass, a variety of laboratory techniques have been developed in order to estimate the rates of total protein and individual contractile protein turnover in the intact experimental animal. These techniques are based on well-established methods of compartmental analysis, and rely on the intravenous administration and biosynthetic incorporation of radiolabeled amino acids into newly synthesized muscle proteins. In this review, the two most widely used procedures (the constant and flooding infusion methods) are examined with respect to the major assumptions and pitfalls in the two procedures. The theoretical and practical limitations of these biosynthetic labeling techniques are critically analyzed with the aim of providing a clear rationale for the application of these techniques to the future study of skeletal and cardiac muscle growth and atrophy in vivo.

Amino Acids↗
PubMed1991

In vivo collagen turnover during development of thyroxine-induced left ventricular hypertrophy.

Cardiac fibroblasts synthesize large amounts of procollagens, yet only a small fraction of mature collagens accumulate in the extracellular matrix. To determine the roles of intracellular degradation of newly synthesized procollagens and extracellular degradation of mature collagens during normal growth and during thyroxine-induced left ventricular hypertrophy, in vivo left ventricular procollagen synthetic rates were assessed in control rats and rats treated with L-thyroxine for 1, 2, 4, and 8 wk (1 mg.kg-1.day-1). A modification of the flooding infusion method was developed using measurements of cardiac prolyl-tRNA, and tissue-free and protein-bound hydroxyproline specific radioactivities 60 min after intravenous administration of a massive dose of [3H]proline. Degradative rates of newly synthesized procollagens and mature collagens were then derived as the difference between rates of procollagen synthesis and collagen accumulation. Left ventricular procollagen synthetic rates were markedly increased after 1 wk of hormone administration (256 +/- 16 and 166 +/- 13 micrograms/day per left ventricle for thyroxine-treated and control animals, respectively; P less than 0.01). An even greater increase in procollagen synthetic rates was observed after 8 wk (438 +/- 46 and 202 +/- 18 micrograms/day for thyroxine-treated and control animals, respectively; P less than 0.01). Despite increased procollagen synthesis, disproportionate accumulation of fibrillar collagens (assessed as the relative concentration of protein-bound hydroxyproline in left ventricular tissue) did not occur. Derived left ventricular degradative rates for newly synthesized procollagens as well as for mature collagens were increased in thyroxine-treated animals. Increased procollagen synthesis, enhanced flux of newly synthesized procollagens through intracellular degradative pathways, and extensive extracellular matrix remodeling without disproportionate collagen accumulation are characteristics of this form of "physiological" left ventricular hypertrophy.

Animals↗
PubMed1991

Contractile activity modulates myosin heavy chain-beta expression in neonatal rat heart cells.

To determine whether spontaneous contractile activity affected the expression of myosin heavy chain isoenzymes in cultured neonatal rat heart cells, ventricular myocytes were isolated from 2-day-old rat pups by collagenase digestion and cultured for 24-96 h in the presence and absence of verapamil (10 microM), KCl (50 mM), or dihydropyridine receptor antagonists that produced contractile arrest. Inhibition of spontaneous contractile activity was associated with significant reductions in total myosin heavy chain (MHC) content and synthetic rates. Electrophoretic analysis of MHC isoenzymes indicated that MHC-beta protein rapidly disappeared from arrested cells, whereas MHC-alpha isoenzyme levels were less affected. In association with these protein changes, mRNA transcript levels for MHC-beta were markedly reduced in quiescent cells, whereas mRNA transcript levels for several other contractile protein genes were relatively less affected. Inhibition of contractile activity and MHC-beta expression were reversible upon removal of the arresting agents. Furthermore, the decrease in MHC-beta mRNA levels in arrested myocytes could be prevented by direct activation of protein kinase C with phorbol 12-myristate 13-acetate (without restoration of contractile activity). Conversely, MHC-beta mRNA levels in beating cells were reduced by treatment with staurosporine (a selective protein kinase C inhibitor). Thus contractile arrest (produced by either L-channel blockade or membrane depolarization) inhibited the accumulation of MHC-beta in cultured neonatal rat heart cells via a pretranslational mechanism. These effects may occur in response to the modulation of signaling system(s) involving mechanical "stretch" transduced via protein kinase C.

Animals↗
PubMed1991

Heterotopic cardiac transplantation decreases the capacity for rat myocardial protein synthesis.

Heterotopic cardiac isografts are vascularly perfused hearts that maintain structural and functional integrity for prolonged periods of time. When placed in an infrarenal location, the heart is hemodynamically unloaded and undergoes negative growth, leading to cardiac atrophy. At 7 and 14 days after transplantation, the transplanted heart was decreased in size compared with the in situ heart (p less than 0.001). To assess the possible mechanism(s) to account for this reduction in size we studied in vivo rates of total left ventricular (LV) protein synthesis, total LV RNA content, and 18S ribosomal RNA content by nucleic acid hybridization. The LV protein synthetic rate was 4.7 and 5.3 mg/day in the in situ heart and was significantly decreased to 2.9 and 2.7 mg/day in the transplanted hearts at 7 and 14 days, respectively. LV RNA content of the transplant declined to 53% and 48% of the in situ value at 7 and 14 days, respectively. Hybridization studies revealed that LV 18S ribosomal subunit content was reduced proportionately to total RNA in the heterotopic hearts. As a result of these changes, there was no significant difference in the efficiency of total LV protein synthesis between the in situ and transplanted hearts. The present studies demonstrate that the hemodynamic unloading and cardiac atrophy that is characteristic of heterotopic cardiac transplantation is accompanied by a decrease in LV total RNA content and 18S RNA, resulting in a decreased capacity for myocardial protein synthesis.

Animals↗
PubMed1990

Regional differences in in vivo myocardial protein synthesis in the neonatal rabbit heart.

Left ventricular free wall (LV) myofibrillar proteins accumulate at a rate approximately 2.5 times faster than the rate of right ventricular free wall (RV) proteins during postnatal cardiac development of the rabbit heart. In this study, the contribution of regional differences in in vivo protein synthesis to the differential rates of growth of the RV and LV myocardium was assessed in 4-d, 3-wk, and 9-wk old rabbits. In vivo total protein fractional synthetic rates were measured by a modification of the flooding infusion method, with calculations based upon the rate of equilibration of plasma leucine and cardiac leucyl-tRNA specific radioactivities following intravenous administration of a large dose of labeled amino acid. This method was also applied to the analysis of the fractional synthetic rate of a contractile protein subunit (myosin heavy chain) in the RV and LV of 4-d and 9-wk old rabbits. Accelerated growth of the LV during the first week of postnatal cardiac development was associated with increased total protein fractional synthetic rates (35.3 +/- 3.6 vs. 45.5 +/- 4.7%/day for RV and LV total protein of 4-d old rabbits, respectively). In addition, RV and LV fractional synthetic rates for myosin heavy chain in the same 4-d old rabbits were considerably greater than those values observed for total protein (84.0 +/- 13.1 and 98.4 +/- 16.9%/day for RV and LV myosin heavy chain, respectively. However, the fractional synthetic rates of both total protein and myosin heavy chain in both the RV and LV rapidly declined during the transition from fetal to adult hemodynamics. Thus, regional and developmental differences in myocyte-specific protein synthesis both contribute to the extensive restructuring of ventricular muscle during this period of extremely rapid growth. These differences may be in response to regional and developmental changes in hemodynamic load.

Aging↗
PubMed1989

Protein synthesis and degradation during regression of thyroxine-induced cardiac hypertrophy.

To characterize changes in rates of protein turnover during regression of thyroxine-induced left ventricular hypertrophy, New Zealand White rabbits received intravenous thyroxine (200 micrograms/kg/d) for 9 days. Thyroxine was withheld, and in vivo protein turnover was evaluated on the 10th, 15th and 20th days. Animals not receiving thyroxine served as controls. Heart rate, blood pressure, and rate-pressure product were measured to correlate changes in cardiac work with protein turnover rates during the development and regression of hypertrophy. Thyroxine administration produced left ventricular hypertrophy by increasing the rate of protein synthesis (from 37.9 +/- 8.9 to 64.1 +/- 15.3 mg/day; P less than 0.05) to a greater degree than protein degradation (from 29.8 +/- 8.9 to 48.2 +/- 15.3 mg/day for control and thyroxine-treated animals, respectively; P less than 0.05). Cessation of thyroxine administration resulted in an eventual return of left ventricular mass to that of normally growing control animals. The major observation noted during thyroxine withdrawal was a return of protein synthetic rates to normal. Absolute rates of protein degradation remained elevated, whereas fractional protein degradative rates (i.e. the fraction of total protein degraded per day) were unchanged by the administration and withdrawal of thyroxine. These results indicate that suppression of both physiological and hormone-induced growth following cessation of thyroxine resulted from a decrease in cardiac protein synthetic rates and an increased rate of flux through the protein degradative pathway(s), while fractional rates of protein degradation (and thus average protein half-life) remained unchanged. The development and regression of thyroxine-induced hypertrophy correlated with thyroxine-mediated alterations in cardiac work.

Animals↗