(Circulation. 1999;99:334-337.)
© 1999 American Heart Association, Inc.
Editorial |
ß-Protein Kinase C and Hypertrophic Signaling in Human Heart Failure
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.
Correspondence to Paul C. Simpson, MD, VAMC 111-C-8, 4150 Clement St, San Francisco, CA 94121. E-mail simpson.paul_c{at}sanfrancisco.va.gov
Key Words: Editorials • heart failure • enzymes
In 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 ß-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.2 3 4
Bowling 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, 
and ß
(both the ß1 and ß2
forms), are substantially elevated, by 40% to 70%, in particulate or
"membrane" fractions. Furthermore, the - and ß-PKC proteins
are increased in cardiac myocytes by immunostaining in
tissue sections, and ß1- and
ß2-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, 
-PKC. Finally,
PKC enzyme activity in failing membranes in vitro is elevated markedly
(
4-fold) and is reduced significantly by an inhibitor of
ß-PKC, LY333531. Overall, the results support a model of enhanced
transcription of the ß-PKC gene in failing human cardiac myocytes,
with consequent elevation in intact ß1- and
ß2-PKC proteins; -PKC might fit the same
model, whereas -PKC might not. The authors speculate that the
increase in - and ß-PKC might signify a role for the
Ca2+-sensitive PKC isoforms in the mechanisms of
heart failure and that the ß-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, , ß1,
ß2, and 
; ß1 and
ß2 are C-terminal splice variants from the same
gene); by DAG but not Ca2+ (the novel or nPKCs,
, , 
, 
/L, and possibly µ or PKD); and by phospholipids
but not Ca2+ or DAG (the atypical or aPKCs, 
,
/
). 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 ß-PKC is
present, but the study by Bowling et al and many others suggest
caution with negative results.1 5 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 1-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 ß-PKC isoform in particular, has come from the overexpression approach, first in cultured myocytes and more recently in the transgenic mouse. ß-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 ß-PKC, when activated, translocates to the perinuclear region in myocytes, where it might regulate transcription.5 7
To test ß-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 ß2-PKC causes robust
induction of the promoters of ß-myosin heavy chain (MHC) and skeletal
-actin, 2 marker genes for transcriptional signaling in
hypertrophy, and furthermore, ß-PKC induces each promoter
through a DNA sequence called the M-CAT.9 10
M-CATs are required for promoter activation by
1-adrenergic and other hypertrophic
stimuli,9 10 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 ß-PKC as an
intermediary in a pathway for activation of cardiac transcription, at
least in a culture model.
Evidence that ß-PKC is also important for hypertrophy in
the intact animal comes from recent transgenic experiments, in which
ß-PKC was overexpressed specifically in cardiac myocytes with the
-MHC promoter. A 10- to 20-fold overexpression of intact
ß2-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 ß-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 ß-PKC inhibitor LY333531 from 3
to 11 weeks prevents hypertrophy and improves necrosis and
fractional shortening, supporting a direct relation between ß-PKC and
the pathological phenotype.
Overexpression of the constitutively activated ß2-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 ß-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 1-adrenergic receptor, or of
Gq, which couples this receptor and others to
increased DAG, both cause myocardial and myocyte
hypertrophy, whereas increased ß-adrenergic signaling
does not.3 13 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.14
Thus, the culture and transgenic studies taken together begin to
suggest one pathway for hypertrophic signaling involving ß-PKC.
Gq-coupled and other receptors are
activated by 1-adrenergic
catecholamines, stretch, and other stimuli; DAG is
increased and PKC is activated; ß-PKC is translocated to the
nucleus; and transcription is stimulated, with subsequent increases in
various proteins and myocyte hypertrophy. The increase in
ß-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 ß-PKC signaling
pathway itself stimulates ß-PKC transcription. In support of this
idea, chronic 1-adrenergic stimulation in
myocytes increases cPKC abundance15 and induces
transcription of another molecule in the pathway, an
1 receptor subtype.16 In
this way, a pathway could regulate its own activity via autoinduction
and maintain hypertrophic signaling over long
times.16
In summary, direct and indirect data and a plausible model implicate ß-PKC as one rate-limiting molecular switch in hypertrophic signaling. A drug has been synthesized that inhibits ß-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 ß-PKC and hypertrophic signaling story, and further work might uncover even better drug targets. The ß-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-1ß 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 ß-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 ß-PKC can kill myocytes, as seen in the mouse
overexpressing intact ß2-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
ß2-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 -PKC
staining of intercalated disks in human
cardiomyopathy. The -PKC isoform is increased in
the ß2-PKC–overexpresser
mouse,11 and thus -PKC could be one target of
ß-PKC–stimulated transcription. Could it be that -PKC at
intercalated disks is causing some mischief, both in human
cardiomyopathy and in the
ß2-PKC mouse? -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,5 7 an association of -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.5
If 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 ß-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 ß-adrenergic system, in which myocyte ß-adrenergic signaling is decreased markedly in heart failure, yet additional ß-antagonism is paradoxically beneficial. Benefit might conceivably result in part from blockade of ß-mediated release of pathological cytokines from cardiac fibroblasts,23 whereas some degree of ß-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.4 19 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.3
Myocyte culture models can be used to work out the molecular details of hypertrophic signaling, ie, how exactly various receptors and switches such as ß-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.
Acknowledgments
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.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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.
2. Molkentin JD, Olson EN. GATA4: a novel transcriptional regulator of cardiac hypertrophy? Circulation. 1997;96:3833–3835.
3.
MacLellan WR, Schneider MD. Success in failure:
modeling cardiac decompensation in transgenic mice.
Circulation. 1998;97:1433–1435.
4.
Homcy CJ. Signaling hypertrophy: how many
switches, how many wires? Circulation. 1998;97:1890–1892.
5.
Mochly-Rosen D, Gordon AS. Anchoring proteins for
protein kinase C: a means for isozyme selectivity. FASEB J. 1998;12:35–42.
6.
Ping P, Zhang J, Qiu Y, Tang XL, Manchikalapudi S, Cao
X, Bolli R. Ischemic preconditioning induces selective
translocation of protein kinase C isoforms and in the
heart of conscious rabbits without subcellular redistribution of total
protein kinase C activity. Circ Res. 1997;81:404–414.
7. 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.[Medline] [Order article via Infotrieve]
8.
Kariya K, Karns LR, Simpson PC. Expression of a
constitutively-activated mutant of the ß-isozyme of
protein kinase C in cardiac myocytes stimulates the promoter of the
ß-myosin heavy chain isogene. J Biol Chem. 1991;266:10023–10026.
9.
Kariya K, Karns LR, Simpson PC. An enhancer core
element mediates stimulation of the rat ß-myosin heavy chain
promoter by an 1-adrenergic agonist and
activated ß-protein kinase C in hypertrophy of
cardiac myocytes. J Biol Chem. 1994;269:3775–3782.
10.
Karns LR, Kariya K, Simpson PC. M-CAT, CArG, and Sp1
elements are required for 1-adrenergic
induction of the skeletal -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.
11.
Wakasaki H, Koya D, Schoen FJ, Jirousek MR, Ways DK,
Hoit BD, Walsh RA, King GL. Targeted overexpression of protein kinase C
ß2 isoform in myocardium causes
cardiomyopathy. Proc Natl Acad Sci
U S A. 1997;94:9320–9325.
12. Bowman JC, Steinberg SF, Jiang T, Geenen DL, Fishman GI, Buttrick PM. Expression of protein kinase C ß in the heart causes hypertrophy in adult mice and sudden death in neonates. J Clin Invest. 1997;100:2189–2195.[Medline] [Order article via Infotrieve]
13. Drazner MH, Koch WJ, Lefkowitz RJ. Potentiation of ß-adrenergic signaling by gene transfer. Proc Assoc Am Physicians. 1997;109:220–227.[Medline] [Order article via Infotrieve]
14.
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.
15.
Henrich CJ, Simpson PC. Differential acute and chronic
response of protein kinase C in cultured neonatal rat heart myocytes to
1-adrenergic and phorbol ester stimulation.
J Mol Cell Cardiol. 1988;20:1081–1085.[Medline]
[Order article via Infotrieve]
16.
Rokosh DG, Stewart AFR, Chang KC, Bailey BA, Karliner
JS, Camacho SA, Long CS, Simpson PC.
1-Adrenergic receptor subtype mRNAs are
differentially regulated by 1-adrenergic and
other hypertrophic stimuli in cardiac myocytes in culture and in
vivo: repression of 1B and
1D but induction of
1C. J Biol Chem. 1996;271:5839–5843.
17. 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 ß inhibitor. Science. 1996;272:728–731.[Abstract]
18.
Patten M, Hartogensis WE, Long CS.
Interleukin-1ß is a negative transcriptional regulator of
1-adrenergic induced gene expression in
cultured cardiac myocytes. J Biol Chem. 1996;271:21134–21141.
19.
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 -myosin heavy chain
in rat hearts. J Clin Invest. 1997;100:1742–1749.[Medline]
[Order article via Infotrieve]
20. 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 Cß2 decreases cardiomyocyte calcium responsiveness and contractility in transgenic mouse hearts. J Clin Invest. 1998;102:72–78.[Medline] [Order article via Infotrieve]
21.
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.
22.
Savart M, Verret C, Dutaud D, Touyarot K, Elamrani N,
Ducastaing A. Isolation and identification of a
µ-calpain-protein kinase C complex in skeletal muscle.
FEBS Lett. 1995;359:60–64.[Medline]
[Order article via Infotrieve]
23. Long CS, Hartogensis WE, Simpson PC. ß-Adrenergic stimulation of cardiac non-myocytes augments the growth-promoting activity of non-myocyte conditioned medium. J Mol Cell Cardiol. 1993;25:915–925.[Medline] [Order article via Infotrieve]
24.
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.
This article has been cited by other articles:
 |
|
 |
|
  D. L. Rigor, N. Bodyak, S. Bae, J. H. Choi, L. Zhang, D. Ter-Ovanesyan, Z. He, J. R. McMullen, T. Shioi, S. Izumo, et al. Phosphoinositide 3-kinase Akt signaling pathway interacts with protein kinase C{beta}2 in the regulation of physiologic developmental hypertrophy and heart function Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H566 - H572. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. C. Hool Differential regulation of the slow and rapid components of guinea-pig cardiac delayed rectifier K+ channels by hypoxia J. Physiol., February 1, 2004; 554(3): 743 - 754. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Guo, M. H. Wu, F. Korompai, and S. Y. Yuan Upregulation of PKC genes and isozymes in cardiovascular tissues during early stages of experimental diabetes Physiol Genomics, January 15, 2003; 12(2): 139 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. K Busk, J. Bartkova, C. C Strom, L. Wulf-Andersen, R. Hinrichsen, T. E.H Christoffersen, L. Latella, J. Bartek, S. Haunso, and S. P Sheikh Involvement of cyclin D activity in left ventricle hypertrophy in vivo and in vitro Cardiovasc Res, October 1, 2002; 56(1): 64 - 75. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Pass, J. Gao, W. K. Jones, W. B. Wead, X. Wu, J. Zhang, C. P. Baines, R. Bolli, Y.-T. Zheng, I. G. Joshua, et al. Enhanced PKCbeta II translocation and PKCbeta II-RACK1 interactions in PKCepsilon -induced heart failure: a role for RACK1 Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2500 - H2510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. B. Roman, D. L. Geenen, M. Leitges, and P. M. Buttrick PKC-{beta} is not necessary for cardiac hypertrophy Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2264 - H2270. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. C. Hool Hypoxia Increases the Sensitivity of the L-Type Ca2+ Current to {beta}-Adrenergic Receptor Stimulation via a C2 Region-Containing Protein Kinase C Isoform Circ. Res., December 8, 2000; 87(12): 1164 - 1171. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-G. Shin, J. V. Barnett, P. Chang, S. Reddy, D. C. Drinkwater, R. N. Pierson, R. G. Wiley, and K. T. Murray Molecular heterogeneity of protein kinase C expression in human ventricle Cardiovasc Res, November 1, 2000; 48(2): 285 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-F. Deng, D. G. Rokosh, and P. C. Simpson Autonomous and Growth Factor-Induced Hypertrophy in Cultured Neonatal Mouse Cardiac Myocytes : Comparison With Rat Circ. Res., October 27, 2000; 87(9): 781 - 788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. He, G. Wu, and M. C. Lapointe Isoproterenol and cAMP regulation of the human brain natriuretic peptide gene involves Src and Rac Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E1115 - E1123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. He and M. C. LaPointe Interleukin-1{beta} Regulates the Human Brain Natriuretic Peptide Promoter via Ca2+-Dependent Protein Kinase Pathways Hypertension, January 1, 2000; 35(1): 292 - 296. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O.-E. Brodde and M. C. Michel Adrenergic and Muscarinic Receptors in the Human Heart Pharmacol. Rev., December 1, 1999; 51(4): 651 - 690. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Walsh Calcineurin Inhibition as Therapy for Cardiac Hypertrophy and Heart Failure : Requiescat in Pace? Circ. Res., April 2, 1999; 84(6): 741 - 743. [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Wang, B. Nolan, W. Kutschke, and J. A. Hill Na+-Ca2+ Exchanger Remodeling in Pressure Overload Cardiac Hypertrophy J. Biol. Chem., May 18, 2001; 276(21): 17706 - 17711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. G. Stebbins and D. Mochly-Rosen Binding Specificity for RACK1 Resides in the V5 Region of beta II Protein Kinase C J. Biol. Chem., August 3, 2001; 276(32): 29644 - 29650. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||