Biochemical and Cellular Changes in Cardiac Hypertrophy

Rabinowitz, Murray; Zak, Roksana

doi:10.1146/annurev.me.23.020172.001333

Cited by 124 publications

(32 citation statements)

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“…Protein degradation is thought to be increased significantly during some interventions that produce net catabolism of skeletal muscle; 31 it often has been assumed that the heart responds similarly, 4 although few actual measurements have been available. In a study closely related to the present one, but dealing with primary atrophy rather than regression of hypertrophy, Hjalmarson, Morgan, and their co-workers 26 measured rates of protein synthesis and degradation following hypophysectomy.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and degradation of myocardial protein during the development and regression of thyroxine-induced cardiac hypertrophy in rats.

Sanford¹,

Griffin²,

Wildenthal³

1978

Circulation Research

111

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SUMMARY Cardiac hypertrophy was induced in rats by daily injections of L-thyroxine (1.0 mg/kg).Regression from hypertrophy was studied 4 days after discontinuing thyroxine. Isolated, Langendorffperfused hearts were perfused with Krebs-Henseleit buffer, glucose, insulin, and amino acids. To measure protein synthesis, left ventricular tissue was assayed for incorporation of tritiated phenylalanine into protein. Indices of rates of protein degradation were obtained by measuring the release of cold phenylalanine after blocking protein synthesis with cycloheximide. After 3 days of thyroxine (when cardiac growth was maximally increased), the rate of protein synthesis increased by 22% (P < 0.001). After 1 week, synthesis was 8% greater than control (P < 0.05), and by 2 weeks (when hypertrophy was stable and the rate of cardiac growth was similar to controls), synthesis had returned to control levels. In hearts regressing from hypertrophy, synthesis was reduced to 68% of control (P < 0.001). The rate of protein degradation was decreased by 12% ( P < 0.05) after 3 days of thyroxine, but was not different from control at 1 or 2 weeks. During regression, degradation was 12% below control (P < 0.05). Changes in the release of several amino acids that are synthesized or metabolized in heart (e.g., alanine, glycine, serine) were different from changes in phenylalanine release. In conclusion thyroxine-induced cardiac hypertrophy and regression are accompanied by changes in protein synthesis and degradation, and amino acid metabolism. The predominant change in hypertrophy is increased protein synthesis with a minor contribution from reduced degradation. Regression of hypertrophy is accompanied by decreased synthesis, not increased degradation.THEORETICALLY, cardiac hypertrophy may occur as a consequence of increased protein synthesis, reduced protein degradation, or both. Similarly, a decrease in heart size, as in regression of hypertrophy, might be brought about by accelerated protein degradation, a decreased rate of synthesis, or both.The relative importance of these factors is defined imprecisely. There is a general agreement that protein synthesis is accelerated during the development of hypertrophy, 1 " 5 but reports differ regarding whether rates of degradation are retarded 5 or not. 23 The type and magnitude of changes that occur may depend on the nature, intensity, and duration of the stress imposed on the heart, and on whether or not the hypertrophic process is accompanied by cellular damage and/or repair.To clarify the roles of altered synthesis and degradation of cardiac protein in one experimental model of hypertrophy and regression, we have measured their rates in vitro following induction and Received January 13, 1978; accepted for publication July 12, 1978. cessation of a well-defined stimulus to hypertrophy-daily injections of L-thyroxine in rats. The regimen employed produces rapid growth of the heart (over and above that observed in age-matched controls), predominantly involving myocardial cells and without...

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Section: Discussionmentioning

confidence: 99%

Synthesis and degradation of myocardial protein during the development and regression of thyroxine-induced cardiac hypertrophy in rats.

Sanford¹,

Griffin²,

Wildenthal³

1978

Circulation Research

111

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“…When stimulated to increased function, many organs respond by growing larger. Such growth may involve hypertrophy (increased cell size) or hyperplasia (increased cell division) or both (1). The initial stimulus to growth may be mediated through the nervous (2) or endocrine (3) system or by chemical changes produced by the stressed cells themselves.…”

mentioning

confidence: 99%

Molecular signals for initiating protein synthesis in organ hypertrophy.

Hammond¹,

Wieben²,

Markert³

1979

Proc. Natl. Acad. Sci. U.S.A.

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When chronically provoked to increased physiologic activity, organs increase in mass through augmented protein synthesis. This process of compensatory hypertrophy can involve cell division as well as cell growth. To test for molecules that might regulate organ size, by inducing hypertrophy, we performed a series of experiments using isolated, perfused, canine hearts in which theleft ventricle was beating but performed no work. Hypertrophying hearts and kidneys as well as normal control organs were extracted and the extracts were perfused through isolated heart preparations. Before and after perfusion, RNA was extracted from fragments of the isolated hearts and translated in cell-free media containing [3sSlmethi-onine. Incorporation of methionine into protein was measured by liquid scintillation spectrometry. WCen erfused through normal hearts, extracts from hypertrophying heart and kidney were able to increase greatly the translational ability of RNA extracted from the normal hearts; corresponding perfusates from nonhypertrophying hearts and kidneys had no effect. Our results indicate that molecules that initiate hypertrophic organ growth are extractable, are generated by the cells of the organ under stress, and are probably similar in heart and kidney and perhaps in many other organs as well. When stimulated to increased function, many organs respond by growing larger. Such growth may involve hypertrophy (increased cell size) or hyperplasia (increased cell division) or both (1). The initial stimulus to growth may be mediated through the nervous (2) or endocrine (3) system or by chemical changes produced by the stressed cells themselves. Determination of organ size is critically important to the structure and function of an organism, and the problem of hypertrophic growth regulation has attracted the attention of investigators for many years.Several hypotheses can be advanced to account for the regulation of organ size: (i) stimulating or inhibiting molecules released by the target organ and acting in feedback loops upon the organ have often been suggested as a basic mechanism for fixing organ size in accord with the physiological needs of the organism (4, 5); (ii) growth may occur as a consequence of the production of specific kinds of molecules (6, 7) within the target cells themselves without the involvement of any circulating molecules; (iii) shifting patterns of metabolic events may bring functional activity and size into concordance, with changes in the proportions of existing molecular species but without the production of regulatory molecules (8, 9). In an attempt to test these various hypotheses and to discover substances that might be involved in regulating organ size, we performed a series of experiments using the canine heart as a target organ.The muscle cells of mammalian hearts do not increase in number after birth, but they do increase in size in response to increased work loads-that is, the heart hypertrophies. An early biochemical indication of impending hypertrophy is increased RNA synt...

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“…Since turnover rate would be an important factor, it should be noted that myosin has completely turned over in the time interval we studied if published rates are correct. 6 However, it seems that alterations in myosin are subtle, since no gross distortions or tendency to aggregation could be detected from Schlieren patterns and amino acid compositions were the same except for the single change noted. That generalized alterations of contractile proteins do no occur is supported by the fact that actin amino acid compositions were identical in all preparations.…”

Section: Discussionmentioning

confidence: 93%

“…Structural abnormalities 4 and altered contractile and regulatory protein function 5 ' 6 have been demonstrated in the hypertrophied and failing heart and postulated to be causally related to the decreased contractile function. In particular, substantial evidence documenting altered activity of various adenosine triphosphatase (ATPase) systems isolated from failing or hypertrophied hearts or both has accumulated and suggests that an abnormality of energy release is responsible for the mechanical dysfunction.…”

mentioning

confidence: 99%

“…We suggest there is a basic alteration in protein metabolism during cardiac hypertrophy and failure that results in the appearance of proteins different from normal populations, since protein metabolism is altered early in hypertrophy and failure. 6 This may cause altered function because of intrinsic differences in the activity-structure relationship (isozyme formation), susceptibility to proteolysis that is not present in normal proteins, or possibly the presence of different proteolytic enzymes that modify existing proteins.…”

mentioning

confidence: 99%

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The amino acid composition of actin and myosin and Ca2+-activated myosin adenosine triphosphatase in chronic canine congestive heart failure.

Raszkowski¹,

Welty²,

Peterson³

1977

Circulation Research

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SUMMARY The Ca2+ -activated myosin ATPase and the amino acid compositions of actin and myosin were determined for preparations from chronically failing dog hearts. Hypertrophy and congestive heart failure were produced by combined tricuspid valve insufficiency and pulmonary artery stenosis. Control, shamoperated, and noncardiac circulatory failure (inferior vena cava constriction) dogs also were studied. All hearts were divided into right ventricle, septum, and left ventricle and each sample was individually analyzed. Calcium-activated ATPase decreased in the failing hearts and showed a distinct gradient of depression from right to left ventricles. There were no changes in ATPase activity among the other groups. The amino acid composition of actin was the same regardless of origin. The amino acid composition of myosin was unaltered except that cystine/2 residues were markedly decreased in failing heart myosin. The same gradient of depression was present as was found for Ca 2 -activated myosin ATPase. This study suggests that protein metabolism is abnormal and that altered proteins are produced in hypertrophy and congestive heart failure. It appears that these changes do not affect all proteins, since actin was normal by the parameters studied. It is clear that the stressed ventricle is the most severely involved, but the entire heart is altered to some degree. Thus, we conclude that altered protein metabolism may be an important primary factor in the genesis of heart failure.ALTHOUGH the contracility of hypertrophied and failing myocardium is decreased 1 " 3 the mechanism responsible for this alteration of physiological function is unknown. Structural abnormalities 4 and altered contractile and regulatory protein function 5 ' 6 have been demonstrated in the hypertrophied and failing heart and postulated to be causally related to the decreased contractile function. In particular, substantial evidence documenting altered activity of various adenosine triphosphatase (ATPase) systems isolated from failing or hypertrophied hearts or both has accumulated and suggests that an abnormality of energy release is responsible for the mechanical dysfunction.Although differences in sarcolemmal, 7 ' 8 sarcoplasmic reticulum, 7 ' 9 actomyosin, myosin, and myofibrillar ATPases have been reported, 5 the basis for these alterations remains obscure. This study was designed to evaluate the Ca 2+ -activated myosin ATPase in purified myosin from the chronically failing canine heart and to determine whether changes could be correlated with an alteration in the amino acid composition of myosin. Actin, the other major contractile protein of the heart responsible for the generation of tension, was also isolated from the same tissue sample and the amino acid composition was determined. MethodsAdult mongrel dogs of both sexes, weighing 15-30 kg, were kept and fed as previously described.7 Randomly selected dogs were trained to use a treadmill and were exercised for 2 weeks. Those with normal excise tolerance 10 were catheterized (right and ...

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Biochemical and Cellular Changes in Cardiac Hypertrophy

Cited by 124 publications

References 0 publications

Synthesis and degradation of myocardial protein during the development and regression of thyroxine-induced cardiac hypertrophy in rats.

Synthesis and degradation of myocardial protein during the development and regression of thyroxine-induced cardiac hypertrophy in rats.

Molecular signals for initiating protein synthesis in organ hypertrophy.

The amino acid composition of actin and myosin and Ca2+-activated myosin adenosine triphosphatase in chronic canine congestive heart failure.

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