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• W2079223224 abstract "HomeCirculationVol. 99, No. 3β-Protein Kinase C and Hypertrophic Signaling in Human Heart Failure Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBβ-Protein Kinase C and Hypertrophic Signaling in Human Heart Failure Paul C. Simpson Paul C. SimpsonPaul C. Simpson From the Division of Cardiology and Research Service, Veterans Affairs Medical Center, and the Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco. Search for more papers by this author Originally published26 Jan 1999https://doi.org/10.1161/01.CIR.99.3.334Circulation. 1999;99:334–337In this issue of Circulation, Bowling et al1 present important data on protein kinase C (PKC) in human heart failure. PKC is a candidate rate-limiting molecular switch in what has come to be known as “hypertrophic signaling,” the molecular mechanisms whereby surface and nuclear receptors and their intracellular transducers convert mechanical and soluble growth stimuli into the end product of a bigger cardiac myocyte. Cardiac myocyte hypertrophy is an essential chronic adaptation but is believed to become maladaptive in the so-called “transition from hypertrophy to failure.” Thus, hypertrophic signaling has become a research area of intense interest, with the hope that targeting specific signaling molecules by drugs or even gene therapy might be useful in heart failure. This editorial summarizes the present study in the context of recent data on PKC, particularly the β-isoform of PKC, and considers some unresolved issues and future directions. Recent editorials in this journal have presented variations on the general theme of hypertrophic signaling.234Bowling et al1 studied PKC proteins, mRNAs, and activity in a dozen explanted hearts with end-stage dilated cardiomyopathy, both ischemic and idiopathic, and a similar number of nonfailing control hearts. Using left ventricular free wall samples from failing hearts, they showed by immunoblot that 2 Ca2+-sensitive PKC isoform proteins, α and β (both the β1 and β2 forms), are substantially elevated, by 40% to 70%, in particulate or “membrane” fractions. Furthermore, the α- and β-PKC proteins are increased in cardiac myocytes by immunostaining in tissue sections, and β1- and β2-PKC mRNAs are also higher in failing myocytes by in situ hybridization. Selectivity in upregulation is suggested by unchanged levels of a Ca2+-insensitive PKC isoform, ε-PKC. Finally, PKC enzyme activity in failing membranes in vitro is elevated markedly (≈4-fold) and is reduced significantly by an inhibitor of β-PKC, LY333531. Overall, the results support a model of enhanced transcription of the β-PKC gene in failing human cardiac myocytes, with consequent elevation in intact β1- and β2-PKC proteins; α-PKC might fit the same model, whereas ε-PKC might not. The authors speculate that the increase in α- and β-PKC might signify a role for the Ca2+-sensitive PKC isoforms in the mechanisms of heart failure and that the β-PKC inhibitor LY333531 might have therapeutic benefit. Indeed, there is now a considerable body of evidence that tends to support this idea.PKC is a large family of serine/threonine kinases that are activated by lipid-derived second messengers.5 The PKCs differ in substrate preference in vitro, intracellular localization in vivo, and mode of activation. They are grouped into families that are activated, at least in vitro, by Ca2+ and diacylglycerol (DAG) (the conventional or cPKCs, α, β1, β2, and γ; β1 and β2 are C-terminal splice variants from the same gene); by DAG but not Ca2+ (the novel or nPKCs, δ, ε, θ, η/L, and possibly μ or PKD); and by phospholipids but not Ca2+ or DAG (the atypical or aPKCs, ζ, λ/ι). Which PKCs are present in myocardium and myocytes has been studied primarily at the protein level by use of antibodies, and there has been controversy as to whether β-PKC is present, but the study by Bowling et al and many others suggest caution with negative results.15 Indeed, quantitative immunoblot shows that among 10 isozymes present in rabbit heart, the cPKCs are actually the most abundant, composing ≈75% of total PKC protein.6 Thus, most or all PKC isoforms could be present in myocytes. Furthermore, PKCs are present in all the various cell types within the heart, including myocytes, fibroblasts, endothelial cells, smooth muscle cells, and neurons, as shown by the pleotropic effects of tumor-promoting phorbol esters (eg, phorbol myristate acetate, or PMA), which interact with the DAG binding site on PKC. So far, there is little convincing evidence for myocardial cell–specific expression of these ubiquitous signaling molecules.A role for PKC in cardiac hypertrophic signaling emerged first from culture models of myocyte hypertrophy, in which a variety of soluble and mechanical hypertrophic stimuli have been identified, including α1-adrenergic and other Gq-coupled agonists, peptide growth factors, cytokines, stretch, and others.2 Most or all hypertrophic stimuli directly activate one or more phospholipases, such as phospholipase C, with liberation of DAG and subsequent acute activation of PKC, typically measured as translocation of PKC activity or immunoreactivity from one cellular compartment to another. Potent and prolonged PKC activation by the phorbol ester PMA causes robust myocyte hypertrophy, and a variety of drugs that inhibit PKC can antagonize hypertrophic responses. Thus, PKC activation is a common feature of hypertrophic signaling. But is it causal or an epiphenomenon?More direct evidence for PKC in hypertrophy, and for the β-PKC isoform in particular, has come from the overexpression approach, first in cultured myocytes and more recently in the transgenic mouse. β-PKC was initially of special interest because of its intracellular location. PKC isoforms are translocated to different cellular sites on activation, via binding to various receptors for activated C-kinase, called RACKs, a mechanism that most likely confers different isoform functions.5 A fraction of β-PKC, when activated, translocates to the perinuclear region in myocytes, where it might regulate transcription.57To test β-PKC function in the absence of the usual activators, a constitutively active mutant was made and overexpressed in cultured cardiac myocytes by transfection.8 Overexpression of activated β2-PKC causes robust induction of the promoters of β-myosin heavy chain (MHC) and skeletal α-actin, 2 marker genes for transcriptional signaling in hypertrophy, and furthermore, β-PKC induces each promoter through a DNA sequence called the M-CAT.910 M-CATs are required for promoter activation by α1-adrenergic and other hypertrophic stimuli,910 and a protein that binds to M-CATs, transcriptional enhancer factor-1 (TEF-1), is essential for normal cardiac development. Thus, a case can be made for β-PKC as an intermediary in a pathway for activation of cardiac transcription, at least in a culture model.Evidence that β-PKC is also important for hypertrophy in the intact animal comes from recent transgenic experiments, in which β-PKC was overexpressed specifically in cardiac myocytes with the α-MHC promoter. A 10- to 20-fold overexpression of intact β2-PKC produces a phenotype suggesting a pathological hypertrophy.11 In mice studied at 11 weeks of age, there is diffuse myocyte hypertrophy by histology and concentric hypertrophy by echocardiography (33% increase in left ventricular mass), as well as increased mRNAs for β-MHC, atrial natriuretic factor, and others. However, areas of healing necrosis are also present, fractional shortening is reduced, and mortality at 20 weeks is higher. Remarkably, oral treatment with the β-PKC inhibitor LY333531 from 3 to 11 weeks prevents hypertrophy and improves necrosis and fractional shortening, supporting a direct relation between β-PKC and the pathological phenotype.Overexpression of the constitutively activated β2-PKC mutant only in adult mouse myocytes by use of a conditional system also causes hypertrophy.12 Turning on transgene expression at 8 to 10 weeks of age causes mild myocyte and myocardial hypertrophy (20% to 25% increase in heart weight) that increases gradually over 9 months. In this model, in which the overexpressed PKC protein is below the level of detection, there is no necrosis or fibrosis, no change in whole-heart abundance of the mRNAs for β-MHC, atrial natriuretic factor, or SERCA2, and no alteration in Ca2+-dependent myofibrillar ATPase. However, open-chest hemodynamics in the basal state and after isoproterenol are impaired, consistent with a pathological phenotype.Hypertrophy is also seen in mice transgenic for upstream signaling molecules in the PKC pathway. Overexpression of an activated α1-adrenergic receptor, or of Gq, which couples this receptor and others to increased DAG, both cause myocardial and myocyte hypertrophy, whereas increased β-adrenergic signaling does not.313 And in a very important converse experiment, overexpression of a peptide that blocks Gq signaling antagonizes hypertrophy in response to the stimulus of pressure overload.14Thus, the culture and transgenic studies taken together begin to suggest one pathway for hypertrophic signaling involving β-PKC. Gq-coupled and other receptors are activated by α1-adrenergic catecholamines, stretch, and other stimuli; DAG is increased and PKC is activated; β-PKC is translocated to the nucleus; and transcription is stimulated, with subsequent increases in various proteins and myocyte hypertrophy. The increase in β-PKC abundance in hypertrophied human hearts and myocytes in the study by Bowling et al1 is consistent with the importance of this pathway and might further reflect a positive feedback mechanism. That is, perhaps the β-PKC signaling pathway itself stimulates β-PKC transcription. In support of this idea, chronic α1-adrenergic stimulation in myocytes increases cPKC abundance15 and induces transcription of another molecule in the pathway, an α1 receptor subtype.16 In this way, a pathway could regulate its own activity via autoinduction and maintain hypertrophic signaling over long times.16In summary, direct and indirect data and a plausible model implicate β-PKC as one rate-limiting molecular switch in hypertrophic signaling. A drug has been synthesized that inhibits β-PKC with high affinity, LY333531, and this drug is already known to improve vascular abnormalities in diabetic rats.17 LY333531 effects in natural models of myocardial hypertrophy and failure will be of great interest, and these experiments are in progress (Chris J. Vlahos, PhD, personal communication, August 4, 1998). This is exciting news and is an excellent example of basic cardiac research progressing to drug development.On the other hand, there are still some important unresolved issues in the β-PKC and hypertrophic signaling story, and further work might uncover even better drug targets. The β-PKC transgenic mice and the many others generated recently should be more tractable than natural models for probing one of the central unresolved questions in the field: what distinguishes adaptive and maladaptive hypertrophy? It appears now that myocytes are virtually awash in a sea of growth stimuli, activating interconnected signaling cascades of serine/threonine and tyrosine phosphorylations that finally converge on rate-limiting steps in transcription, translation, and protein degradation. It seems very likely that varying combinations of pathways will be more or less active in different settings and that very different molecular and functional hypertrophic phenotypes will result. For instance, signaling by the cytokine interleukin-1β causes myocyte hypertrophy with no increase in contractile proteins, probably via inhibition of myocyte-specific transcription, a form of hypertrophy that seems clearly pathological.18 In contrast, thyroid hormone signaling increases hypertrophy but reverses or prevents pathological function in pressure overload, most likely through an effect on myocyte transcription, illustrating again that “hypertrophy” is not necessarily bad but rather can be physiological or adaptive.19 A spectrum of physiological and pathological phenotypes probably exists, and a theoretical goal in therapy would be to mimic physiological signaling and to inhibit pathological signaling.Could an intracellular transducer like β-PKC, which is activated by many growth stimuli, have both adaptive and maladaptive effects, and by what mechanism? It certainly appears that very high levels of β-PKC can kill myocytes, as seen in the mouse overexpressing intact β2-PKC from birth.11 Possibly, overstimulation of transcription simply causes myocytes to get “too big” and die, but there is little to support this idea, and perhaps something else is going on. For example, further work with the β2-PKC overexpresser mouse suggests that isolated myocytes have contractile dysfunction, with reduced myofilament Ca2+-responsiveness, possibly due to hyperphosphorylation of troponin I.20 Could this somehow kill cells, either directly or indirectly? Alternatively, a striking finding in the study by Bowling et al1 is a marked increase in α-PKC staining of intercalated disks in human cardiomyopathy. The α-PKC isoform is increased in the β2-PKC–overexpresser mouse,11 and thus α-PKC could be one target of β-PKC–stimulated transcription. Could it be that α-PKC at intercalated disks is causing some mischief, both in human cardiomyopathy and in the β2-PKC mouse? α-PKC substrate(s) at the intercalated disk will be of great interest. Finally, very intense PKC activation, as with PMA, causes loss of myofibrils in myocytes,21 and high levels of PKC might mimic PMA. Myofibril loss is a common finding in end-stage human cardiomyopathy, and possible mechanisms include an unwanted side effect of a PKC isoform that localizes to sarcomeres,57 an association of α-PKC with a Ca2+-dependent protease,22 and/or unregulated PKC catalytic activity.15 Consideration of various toxic side effects of PKC activation is more than just idle speculation, because the way is now open to develop agents that modulate PKC functions very selectively in myocytes.5If PKC actions within myocytes are complex, they are even more so in the intact heart with multiple cell types. As noted above, most cells contain many PKC isoforms, and indeed, the β-PKC antagonist LY333531 is thought to have beneficial effects in diabetes by inhibition of vascular PKC.17 The ubiquity of PKC needs to be kept in mind in interpretation of the effects of drugs in the intact animal, and it is conceivable that PKC inhibition could have beneficial effects in one cell type and adverse effects in another. A possible example of opposing effects in drug action is found in the β-adrenergic system, in which myocyte β-adrenergic signaling is decreased markedly in heart failure, yet additional β-antagonism is paradoxically beneficial. Benefit might conceivably result in part from blockade of β-mediated release of pathological cytokines from cardiac fibroblasts,23 whereas some degree of β-adrenergic augmentation in myocytes might actually be helpful.13 Consideration of cell-specific effects is important.Several major lines of future investigation might begin to unravel these issues. In transgenic models, the levels and activities of overexpressed proteins need to be correlated with molecular and functional outcomes. This has so far been done mostly at the tissue level and should be extended to isolated myocytes to avoid technical problems, such as nonmyocyte contamination,23 dilution artifacts from cellular hypertrophy,19 heterogeneous or time-dependent transgene expression, and load effects on function. We need better molecular markers for physiological and pathological myocyte function.419 Isolated human myocytes can now be studied in a similar way,24 and relative levels of a signaling molecule in human nonfailing and failing heart samples can be compared with mouse models. It is self-evident in biology that dose is important (“too much of anything is bad for you”), and therefore, it is possible that some effects in transgenic models are a consequence of levels of signaling activity not encountered even in human disease.3Myocyte culture models can be used to work out the molecular details of hypertrophic signaling, ie, how exactly various receptors and switches such as β-PKC regulate the myocyte phenotype. Myocytes cultured from knockout hearts might be particularly informative in this regard. Certainly, work in the field has identified some important signaling molecules, but others more potent and/or selective could well exist. Mechanisms of transcriptional signaling should be of special importance, because transcriptional drugs might target myocytes selectively. It is also critical to identify the substrates and mechanisms for toxic side effects of hypertrophic signaling, as suggested for PKC.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Work in the author’s laboratory is supported by the NIH, the AHA, and the Department of Veteran’s Affairs Research Service. I thank Carlin S. Long for review of the manuscript.FootnotesCorrespondence to Paul C. Simpson, MD, VAMC 111-C-8, 4150 Clement St, San Francisco, CA 94121. E-mail [email protected] References 1 Bowling N, Walsh RA, Song G, Estridge T, Sandusky GE, Fouts RL, Mintze K, Pickard T, Roden R, Bristow MR, Sabbah HN, Mizrahi JL, Gromo G, King GL, Vlahos CJ. Increased protein kinase C activity and expression of Ca2+-sensitive isoforms in the failing human heart. Circulation.1998; 98:384–391.Google Scholar2 Molkentin JD, Olson EN. GATA4: a novel transcriptional regulator of cardiac hypertrophy? Circulation.1997; 96:3833–3835.MedlineGoogle Scholar3 MacLellan WR, Schneider MD. Success in failure: modeling cardiac decompensation in transgenic mice. Circulation.1998; 97:1433–1435.CrossrefMedlineGoogle Scholar4 Homcy CJ. Signaling hypertrophy: how many switches, how many wires? Circulation.1998; 97:1890–1892.CrossrefMedlineGoogle Scholar5 Mochly-Rosen D, Gordon AS. Anchoring proteins for protein kinase C: a means for isozyme selectivity. FASEB J.1998; 12:35–42.CrossrefMedlineGoogle Scholar6 Ping P, Zhang J, Qiu Y, Tang XL, Manchikalapudi S, Cao X, Bolli R. Ischemic preconditioning induces selective translocation of protein kinase C isoforms ε and η in the heart of conscious rabbits without subcellular redistribution of total protein kinase C activity. Circ Res.1997; 81:404–414.CrossrefMedlineGoogle Scholar7 Mochly-Rosen D, Henrich CJ, Cheever L, Khaner H, Simpson PC. A protein kinase C isozyme is translocated to cytoskeletal elements on activation. Cell Regul.1990; 1:693–706.CrossrefMedlineGoogle Scholar8 Kariya K, Karns LR, Simpson PC. Expression of a constitutively-activated mutant of the β-isozyme of protein kinase C in cardiac myocytes stimulates the promoter of the β-myosin heavy chain isogene. J Biol Chem.1991; 266:10023–10026.CrossrefMedlineGoogle Scholar9 Kariya K, Karns LR, Simpson PC. An enhancer core element mediates stimulation of the rat β-myosin heavy chain promoter by an α1-adrenergic agonist and activated β-protein kinase C in hypertrophy of cardiac myocytes. J Biol Chem.1994; 269:3775–3782.CrossrefMedlineGoogle Scholar10 Karns LR, Kariya K, Simpson PC. M-CAT, CArG, and Sp1 elements are required for α1-adrenergic induction of the skeletal α-actin promoter during cardiac myocyte hypertrophy: transcriptional enhancer factor-1 and protein kinase C as conserved transducers of the fetal program in cardiac growth. J Biol Chem.1995; 270:410–417.CrossrefMedlineGoogle Scholar11 Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK, Hoit BD, Walsh RA, King GL. Targeted overexpression of protein kinase C β2 isoform in myocardium causes cardiomyopathy. Proc Natl Acad Sci U S A.1997; 94:9320–9325.CrossrefMedlineGoogle Scholar12 Bowman JC, Steinberg SF, Jiang T, Geenen DL, Fishman GI, Buttrick PM. Expression of protein kinase C β in the heart causes hypertrophy in adult mice and sudden death in neonates. J Clin Invest.1997; 100:2189–2195.CrossrefMedlineGoogle Scholar13 Drazner MH, Koch WJ, Lefkowitz RJ. Potentiation of β-adrenergic signaling by gene transfer. Proc Assoc Am Physicians.1997; 109:220–227.MedlineGoogle Scholar14 Akhter SA, Luttrell LM, Rockman HA, Iaccarino G, Lefkowitz RJ, Koch WJ. Targeting the receptor-Gq interface to inhibit in vivo pressure overload myocardial hypertrophy. Science.1998; 280:574–577.CrossrefMedlineGoogle Scholar15 Henrich CJ, Simpson PC. Differential acute and chronic response of protein kinase C in cultured neonatal rat heart myocytes to α1-adrenergic and phorbol ester stimulation. J Mol Cell Cardiol.1988; 20:1081–1085.CrossrefMedlineGoogle Scholar16 Rokosh DG, Stewart AFR, Chang KC, Bailey BA, Karliner JS, Camacho SA, Long CS, Simpson PC. α1-Adrenergic receptor subtype mRNAs are differentially regulated by α1-adrenergic and other hypertrophic stimuli in cardiac myocytes in culture and in vivo: repression of α1B and α1D but induction of α1C. J Biol Chem.1996; 271:5839–5843.CrossrefMedlineGoogle Scholar17 Ishii H, Jirousek MR, Koya D, Takagi C, Xia P, Clermont A, Bursell SE, Kern TS, Ballas LM, Heath WF, Stramm LE, Feener EP, King GL. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC β inhibitor. Science.1996; 272:728–731.CrossrefMedlineGoogle Scholar18 Patten M, Hartogensis WE, Long CS. Interleukin-1β is a negative transcriptional regulator of α1-adrenergic induced gene expression in cultured cardiac myocytes. J Biol Chem.1996; 271:21134–21141.CrossrefMedlineGoogle Scholar19 Chang KC, Figueredo VM, Schreur JHM, Kariya K, Weiner MW, Simpson PC, Camacho SA. Thyroid hormone improves function and Ca2+ handing in pressure overload hypertrophy: association with increased sarcoplasmic reticulum Ca2+-ATPase and α-myosin heavy chain in rat hearts. J Clin Invest.1997; 100:1742–1749.CrossrefMedlineGoogle Scholar20 Takeishi Y, Chu G, Kirkpatrick DM, Li Z, Wakasaki H, Kranias EG, King GL, Walsh RA. In vivo phosphorylation of cardiac troponin I by protein kinase Cβ2 decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. J Clin Invest.1998; 102:72–78.CrossrefMedlineGoogle Scholar21 Sussman MA, Hamm-Alvarez SF, Vilalta PM, Welch S, Kedes L. Involvement of phosphorylation in doxorubicin-mediated myofibril degeneration: an immunofluorescence microscopy analysis. Circ Res.1997; 80:52–61.CrossrefMedlineGoogle Scholar22 Savart M, Verret C, Dutaud D, Touyarot K, Elamrani N, Ducastaing A. Isolation and identification of a μ-calpain-protein kinase Cα complex in skeletal muscle. FEBS Lett.1995; 359:60–64.CrossrefMedlineGoogle Scholar23 Long CS, Hartogensis WE, Simpson PC. β-Adrenergic stimulation of cardiac non-myocytes augments the growth-promoting activity of non-myocyte conditioned medium. J Mol Cell Cardiol.1993; 25:915–925.CrossrefMedlineGoogle Scholar24 Dipla K, Mattiello A, Jeevanandam V, Houser SR, Margulies KB. Myocyte recovery after mechanical circulatory support in humans with end-stage heart failure. Circulation.1998; 97:2316–2322.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails January 26, 1999Vol 99, Issue 3Article InformationMetrics Copyright © 1999 by American Heart Associationhttps://doi.org/10.1161/01.CIR.99.3.334 Originally publishedJanuary 26, 1999 Keywordsenzymesheart failureEditorialsPDF download Advertisement" @default.
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• W2079223224 title "β-Protein Kinase C and Hypertrophic Signaling in Human Heart Failure" @default.
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