HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 275, Issue 39, 29927-29930, September 29, 2000

This Article Abstract Full Text (PDF) All Versions of this Article: 275/39/29927    most recent C000380200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, G. Articles by Dorn, G. W. Search for Related Content PubMed PubMed Citation Articles by Wu, G. Articles by Dorn, G. W., II Social Bookmarking                      What's this?

ACCELERATED PUBLICATION
Protein Kinase C in Pathological Myocardial Hypertrophy

ANALYSIS BY COMBINED TRANSGENIC EXPRESSION OF TRANSLOCATION MODIFIERS AND G_q^*

Guangyu Wu, Tsuyoshi Toyokawa, Harvey Hahn, and Gerald W. Dorn II

From the Division of Cardiology, University of Cincinnati, Cincinnati, Ohio 45267

Received for publication, June 13, 2000, and in revised form, July 14, 2000

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

The  isoform of protein kinase C (PKC) has a critical cardiotrophic function in normal postnatal developing heart as demonstrated by cardiac-specific transgenic expression of PKC-selective translocation inhibitor (V1) and activator (RACK) peptides (Mochly-Rosen, D., Wu, G., Hahn, H., Osinska, H., Liron, T., Lorenz, J. N., Robbins, J., and Dorn, G. W., II (2000) Circ. Res. 86, 1173-1179). To define the role of PKC signaling in pathological myocardial hypertrophy, V1 or RACK were co-expressed in mouse hearts with G_q, a PKC-linked hypertrophy signal transducer. Compared with G_q overexpression alone, co-expression of RACK with G_q increased PKC particulate partitioning by 30 ± 2%, whereas co-expression of V1 with G_q reduced particulate-associated PKC by 22 ± 1%. Facilitation of PKC translocation by RACK in G_q mice improved cardiac contractile function measured as left ventricular fractional shortening (30 ± 3% G_q versus 43 ± 2% RACK/G_q, p < 0.05). Conversely, inhibition of PKC by V1 modified the G_q nonfailing hypertrophy phenotype to that of a lethal dilated cardiomyopathy. These opposing effects of PKC translocation activation and inhibition in G_q hypertrophy indicate that PKC signaling is a compensatory event in myocardial hypertrophy, rather than a pathological event, and support the possible therapeutic efficacy of selective PKC translocation enhancement in cardiac insufficiency.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

The protein kinase Cs (PKCs)¹ constitute a large family of ubiquitous phospholipid-dependent serine-threonine kinases postulated to have diverse effects in the heart, including mediating cardiac hypertrophy/failure and myocardial protection (1-3). It has been difficult to establish particular roles for individual PKC isoforms due to the absence of isoform-specific agonists and antagonists. Targeted cardiac overexpression of PKC has been helpful in establishing possible effects of myocardial PKC  signaling (4, 5), but the potential for nonspecific or nonphysiological signaling of overexpressed enzymes warrants a cautious interpretation of resulting phenotypes. Based on recent insights into the mechanism for differential PKC isoform subcellular translocation upon activation (6), a strategy was developed whereby the effects of endogenous myocardial PKC isoforms such as PKC could be elucidated by cardiac-specific expression of peptides that specifically modulate PKC isoform translocation/activation (7, 8). These PKC-derived peptides, RACK (HDAPIGYD, rat PKC amino acids 85-92) and V1 (the first variable region of rat PKC, amino acids 2-144) have previously been shown to specifically modulate PKC translocation (7-9). Compared with transgenic overexpression of PKC, a critical advantage of translocation modification is that PKC isoforms are specifically regulated without changing the natural stoichiometric relationships of PKC to its upstream activators and downstream substrates. Cardiac transgenic models expressing either the PKC translocation inhibitor (V1) or activator (RACK) were previously created with opposing cardiac phenotypes of dilated cardiomyopathy and physiological hypertrophy, respectively (8), demonstrating that PKC signaling is both necessary and sufficient for normal myocardial growth in the developing young mouse. This apparently beneficial role for PKC in normal physiologic cardiac growth is, however, at odds with the widely held notion that pathological cardiac hypertrophy is the consequence of PKC signaling (1, 10-13). In addressing this apparent contradiction, we hypothesized that the effects of PKC on a diseased heart might be different than during normal heart development. We further considered that these putative pathologic effects could be identified using PKC-specific translocation modification in the context of a form of cardiac hypertrophy where PKC is thought to be a pathological mediator, like the cardiac-specific G_q-overexpressing mouse, which develops myocardial hypertrophy and contractile depression associated with PKC translocation (11, 12). V1 or RACK were therefore co-expressed with G_q by cross-breeding the respective individual transgenic mice to generate compound transgenic mice.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Transgenic Models-- Details of transgenic mice (FVB/N background) overexpressing G_q, V1, or RACK under control of the full-length mouse myosin heavy chain (MHC) promoter have previously been described (7, 8, 11). G_q mice express G_q at ~5 times nontransgenic levels (the line previously described as G_q-40) and develop nonfailing ventricular hypertrophy with modest contractile depression, which is unresponsive to -adrenergic agonists (11). RACK transgenic mice develop mild hypertrophy with normal ventricular function and normal response to -adrenergic agonists (7, 8). The V1_low (lowest expressing) mice used herein have normal cardiac mass and function, whereas higher expressing V1 lines develop ventricular dilation with wall thinning, diminished systolic function, and heart failure (8). Compound transgenic mice overexpressing V1 or RACK and G_q were obtained by breeding heterozygous V1_low or RACK with heterozygous G_q-40 mice. Transgenes, alone and in combination, were identified by genomic Southern analysis of tail clip DNA. All experiments were performed with comparison of littermates.

Western Blot Analysis-- Samples for measurement of transgene products and PKC expression were prepared as described previously (12). Briefly, mouse ventricles frozen at 80 °C were homogenized in buffer (50 mM Tris-HCl, pH 7.5, 5 mM EDTA, 10 mM EGTA, 5 mM dithiothreitol, 10 mM benzamidine, 0.5 mM phenylmethylsulfonyl fluoride, 10 µg/ml pepstatin, 10 µg/ml aprotinin, and 10 µg/ml leupeptin) followed by centrifugation at 100,000 × g for 1 h. The pellet was further extracted with buffer containing 1% Triton X-100 for 30 min on ice. Proteins were separated on SDS-polyacrylamide gel electrophoresis and transferred to polyvinylidene difluoride membrane. V1 and G_q transgene expression were evaluated by Western blot analysis using anti-FLAG M2 (Sigma) and anti-G_q/11 (Santa Cruz) monoclonal antibodies, respectively. PKC isoform expression was measured by quantitative immunoblot analysis with anti-PKC (Santa Cruz) and anti-PKC antibodies (Transduction Laboratories) using recombinant human PKC and PKC (Calbiochem) as quantitative standards (8, 12). Protein loading and transfer efficiency were evaluated by amido black staining of the membrane after immunoblotting.

Assessment of Cardiac Hypertrophy and Function-- Morphometric analysis and histological examination of Masson's trichrome-stained ventricles used standard techniques. Echocardiography was performed to determine cardiac contractile function in a noninvasive manner; left ventricular fractional shortening (the proportion of blood ejected during systole compared with maximal ventricular capacity in diastole) and left ventricular mass were calculated (14). Cardiac gene expression was assayed by RNA dot blot analysis using total RNA (3 µg/dot) extracted from ventricles of nontransgenic and transgenic mice and ³²P-labeled oligonucleotides as probes (11). Hybridization was quantified using a Storm PhosphorImager (Molecular Dynamics) and expression of each cardiac gene was normalized to glyceraldehyde-3-phosphate dehydrogenase.

Statistical Analysis-- All data are expressed as mean ± S.E. Comparisons between G_q and dual transgenic mice were evaluated using Student's t test, and the p value of <0.05 was considered as statistically significant. Values for nontransgenic (NTG) siblings are also presented for comparison, but were not included in the statistical analysis.

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Cardiac-targeted transgenic expression of V1 and resulting inhibition of myocardial PKC translocation has proven that PKC activation is necessary for normal physiological myocardial growth in the postnatal period (8). Complementing this finding is the observation that enhancing PKC activation by expression of RACK stimulates growth of normally functioning myocardium (8). Herein, we utilized in vivo translocation modulation to characterize PKC effects in G_q-stimulated cardiac hypertrophy, a form of hypertrophy in which PKC translocation is increased and in which PKC has therefore been considered to be a possible pathological mediator (11, 12). Compound transgenic mice were generated and ventricular expression of V1 and G_q was compared between parent mice and dual transgenic progeny by Western blot analysis (Fig. 1A). Compound transgenic mice expressed both V1 and G_q at the same levels as parent lines, indicating that no cross-talk occurred at the level of transgene expression. As reported previously, it is not possible to detect RACK expression by Western blot analysis due to the small molecular weight of the peptide (8). However, Northern blot analysis showed no change in RACK and G_q transgene expression in compound transgenic mice, compared with parent lines (data not shown).

View larger version (36K): [in this window] [in a new window]   Fig. 1.   A, Western blot analysis of transgene Gq and V1 expression. Representative of three separate experiments with similar results. B, quantitative immunoblot analysis of PKC expression in Gq and compound transgenic RACK/Gq or V1/Gq mice. Representative of four experiments. Group data represent mean ± S.E. for n = 6 per group. C, comparison of PKC translocation in transgenic hearts. Representative of four individual experiments. P, particulate fraction; C, cytosol fraction. *, p < 0.05 versus Gq mice.

G_q activates PKC via phospholipase C (15). As expected from this signaling pathway, myocardial G_q overexpression results in increased PKC partitioning to particulates, i.e. translocation, associated with a decrease in total PKC content which is considered to be a consequence of chronic PKC activation (11, 12). We measured the effects of RACK and V1 on the expression and translocation of PKC in G_q overexpressors using quantitative Western blot analysis. PKC, which is transcriptionally up-regulated but not translocated in G_q overexpressing hearts (12), was also measured to assay the isoform specificity of V1 and RACK. Compared with nontransgenic siblings, RACK and V1 transgenic mice exhibited a 20 ± 3% increase and 15 ± 2% decrease, respectively, of PKC translocation (measured as the paticulate/cytosol ratio) with no change in PKC content (data not shown). This is similar to the initial description of these models (7, 8). As shown in Fig. 1B, combined expression of either RACK or V1 with G_q did not alter the characteristically decreased myocardial PKC content of G_q overexpressors (12) (NTG 163 ± 8 ng/mg, G_q 122 ± 9, RACK/G_q 120 ± 6, n = 4 in each group, p = not significant for RACK/G_q versus G_q; NTG 159 ± 9, G_q 113 ± 12 and V1/G_q 115 ± 10, n = 4 in each group, p = not significant for V1/G_q versus G_q). Fig. 1C shows that particulate partitioning of PKC, which is increased by G_q overexpression (11, 12), was further augmented 30 ± 2% in RACK/G_q mice (particulate/cytosol ratio: NTG 1.2 ± 0.1, G_q 2.1 ± 0.1, RACK/G_q 2.8 ± 0.2, n = 4 in each group, p < 0.05 for RACK/G_q versus G_q) and attenuated by 22 ± 1% in V1/G_q (particulate/cytosol ratio: NTG 1.2 ± 0.1, G_q 2.3 ± 0.1 and V1/G_q 1.8 ± 0.2, n = 4 in each group, p < 0.05 for V1/G_q versus G_q). Expression and translocation of PKC, transcriptionally increased in G_q hearts relative to NTG (12), were not affected in G_q mice by the PKC modifying peptides (PKC content: NTG 852 ± 79 ng/mg, G_q 1259 ± 93 and RACK/G_q 1198 ± 121; NTG 847 ± 125, G_q 1368 ± 110 and V1/G_q 1359 ± 186; particulate/cytosol ratio: NTG 0.44 ± 0.04, G_q 0.42 ± 0.03 and RACK/Gq 0.45 ± 0.03; NTG 0.41 ± 0.04, G_q 0.40 ± 0.01, and V1/G_q 0.40 ± 0.02), confirming the specific effects of these peptides on PKC (7, 9).

RACK/G_q mice were healthy when followed for 5 months. Effects of enhanced PKC translocation/activation on G_q-mediated cardiac hypertrophy and contractile dysfunction were assessed in 12-week-old RACK/G_q mice. Compared with G_q transgenic siblings, ventricular and atrial weights in RACK/G_q mice were reduced (Table I). Left ventricular mass of RACK/G_q mice calculated from noninvasive echocardiographic analysis was correspondingly decreased (Table II). Echocardiography further revealed that RACK/G_q hearts had reduced end diastolic and systolic dimensions, i.e. that the cardiac ventricles were smaller before or after contraction, with no change in left ventricular wall thickness (Table II). Thus, the ratio of wall thickness to ventricular radius (h/r) was increased, which suggests concentric ventricular remodeling. Perhaps as a consequence of this more favorable ventricular geometry, RACK expression enhanced left ventricular contractile function of G_q mice, measured echocardiographically as the proportion of blood volume ejected per cardiac cycle, or fractional shortening (NTG 51 ± 3%, RACK 47 ± 1%, G_q 30 ± 3% and RACK/G_q 43 ± 2%).

View this table: [in this window] [in a new window]   Table II Echocardiographic parameters in NTG, single and dual transgenic mice FS, fractional shortening; ESD, end systolic dimension; EDD, end diastolic dimension; PWT, left ventricular posterior wall thickness; LVM, left ventricular mass; h/r, ratio of wall thickness to heart chamber radius; Change, percentage of increase (+) or decrease () in cross mice relative to Gq mice; R, RACK mice. Values are mean ± S.E. NS, no significance.

A molecular marker of cardiac hypertrophy is increased expression of the embryonic cardiac genes -skeletal actin, -MHC, and atrial netriuretic peptide (ANF) in ventricle (16). These genes are highly expressed in G_q overexpressing hearts (11, 14), and Northern analysis revealed that -skeletal actin gene expression was selectively reduced in ventricles of RACK/G_q mice, whereas ANF and -MHC gene expression was not changed from their characteristically elevated levels (11) (Fig. 2B). Since inhibition of PKC with V1 in normal hearts was previously shown to selectively increase expression of -skeletal actin gene (8), the isolated reduction of this mRNA by RACK in the G_q mice suggests a role for PKC in transcriptionally regulating actin, but not ANF or -MHC expression, in the heart. Taken together, the results with RACK/G_q mice indicate that enhanced PKC translocation improves ventricular function and normalizes ventricular geometry, but surprisingly, diminishes the extent of cardiac hypertrophy in G_q overexpressors.

View larger version (57K): [in this window] [in a new window]   Fig. 2.   A, 12-week-old transgenic mouse hearts showing concentric remodeling in RACK/Gq and dilation in V1/Gq mice. The arrow points to an area of left ventricular wall thinning. B, RNA analysis of gene expression. Quantitative data are indexed to GAPDH (n = 3) and expressed as percent of Gq mice. *, p < 0.05 versus Gq mice. C, representative Masson's trichrome stain of left ventricles showing mild interstitial fibrosis (blue staining) in V1/Gq.

Heart failure is not typically observed in G_q-overexpressing mice, although the characteristic eccentric hypertrophy is associated with measurable contractile depression (11). Heart failure also is not a feature of V1_low mice in which hearts are functionally and histologically normal (8). Thus, breeding G_q with V1_low is the equivalent of crossing two nonfailing cardiac models. Strikingly, combined expression of V1_low with G_q caused development of lethal heart failure at 14 ± 2 weeks of age (n = 9). At 12 weeks of age, V1/G_q mice could not tolerate echocardiographic analysis under even light anesthesia, so a confident assessment of in vivo ventricular function at an age matching that of the RACK/G_q mice was not obtained. However, gross pathological examination of 12-week-old hearts revealed ventricular dilatation, focal ventricular wall thinning, and massively enlarged atria containing intracavitary blood clots, which are typically observed in chronic low cardiac output states, i.e. heart failure (Fig. 2A). These gross pathological findings were much more striking than the histological appearance which revealed only areas of mild myocardial fibrosis, as detected by blue staining with Masson's trichrome (Fig. 2C), Interestingly, V1 overexpression did not alter the program of ANF, -MHC, or -skeletal actin gene expression in G_q mice (Fig. 2B). Since a clear mechanism for development of heart failure was not readily apparent from these postmortem studies, and as 12-week-old mice were too sick to undergo in vivo physiological assessment, we performed echocardiographic examination of apparently healthy 6-week-old V1/G_q mice to help define the relevant pathophysiology. At 6 weeks, V1/G_q hearts exhibited ventricular enlargement and wall thinning with depressed contractile function (fractional shortening) compared with G_q, which at this age have not yet developed contractile dysfunction (Table II). These findings suggested that V1_low inhibits myocardial growth in the young developing G_q mice, as V1_high did in mice with a normal genetic background (8). This notion was confirmed by a 27% reduction in dry ventricular weight of V1/G_q mice, compared with G_q (Table I). In contrast, atrial weight was increased, which, as noted above, probably reflects contractile depression. Finally, the ratio of ventricular wall thickness to ventricular radius (h/r) was significantly diminished, indicating that dilatory remodeling, i.e. ventricular wall thinning with chamber enlargement, was already occurring in 6-week-old V1/G_q mice. Thus, inhibition of PKC translocation, which is already "enhanced" in the Gq mouse, impairs ventricular function, causes cardiac enlargement with ventricular dilatation, and reduces ventricular mass.

The reciprocal cardiac phenotypes of RACK/G_q and V1/G_q mice described above unequivocally refute our hypothesis that PKC signaling contributes to the pathology associated with G_q-mediated hypertrophy. Although PKC activation occurs in G_q hearts, "superactivation" with RACK proved to be therapeutic, whereas even the modest impairment of PKC translocation caused by V1_low, essentially "normalization," greatly exaggerated the underlying G_q pathology. Most surprising is that the opposing effects on cardiac function were not due to opposite effects on cardiac "hypertrophy" per se, in that RACK and V1 both decreased left ventricular mass of G_q mice. Rather, it is apparently an PKC effect on ventricular geometry that is the critical determinant of viability, with benefit accruing from RACK-induced concentric remodeling (of the eccentrically hypertrophied G_q heart (11)) and V1-induced ventricular dilatation proving fatal. These changes in geometry were surprisingly well defined in that they were not associated with significant changes in ANF or -MHC gene expression, which are widely considered to be indices of cardiac pathology (16). In the context of our prior study (8), the current results show that the molecular and morphometric effects of PKC are similar in nontransgenic and G_q overexpressing hearts, but the effects of PKC activation and inhibition are amplified in the G_q model.

An intriguing difference between the current studies of PKC in the G_q background and our previous characterization of PKC translocation modulation in the normal background is the absence of a "hypertrophic" effect of RACK plus G_q. We previously found a modest increase in ventricular mass of 12-week-old RACK mice, with concentric remodeling. Compared with G_q, however, RACK/G_q ventricles were concentrically remodeled, but smaller. This suggests that the intrinsic contractile depression and eccentric remodeling of G_q mice may itself contribute to the hypertrophic response. RACK improved ventricular geometry and function and as a consequence diminished the external stimulus for hypertrophy.

A strength of the current studies is that PKC activity/translocation was modulated by expressing catalytically inactive peptides rather than by overexpressing PKC itself, essentially using transgenesis as a means of organ-specific drug delivery. However, the effects of PKC modulation were measured in the G_q transgenic mouse, which achieves its phenotype by 5-fold increased expression of G_q (11). Thus, concerns regarding stoichiometric excess and nonspecific activity of overexpressed signaling proteins (which drove our unique approach of PKC isoform translocation modification) apply to the G_q model itself. While the rationale for choosing the G_q model is strong, i.e. changes in PKC translocation, which suggested it as a pathological mediator (11, 12), the relevance of G_q overexpression to naturally occurring cardiac disease is uncertain. Additional studies are therefore ongoing to determine the effects of V1 and RACK on cardiac hypertrophy and function in hemodynamically stressed hearts.

In conclusion, the current studies contradict the generally accepted notion that PKC is a pathophysiological mediator of cardiac disease. Rather, they support the notion that PKC translocation, either by direct administration of RACK peptide, by gene therapy, or through novel pharmacological means, could be used to treat heart failure in the same manner that induction of "physiological" hypertrophy by exercise or growth factors has proven to be therapeutic (17).

	FOOTNOTES

^* This work was supported by National Institutes of Health Grants HL58010 and HL52318.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Cardiology, University of Cincinnati Medical Center, 231 Bethesda Ave., Cincinnati, OH 45267-0542. Tel.: 513-558-3065; Fax: 513-558-3060; E-mail: dorngw@ucmail.uc.edu.

Published, JBC Papers in Press, July 17, 2000, DOI 10.1074/jbc.C000380200

	ABBREVIATIONS

The abbreviations used are: PKC, protein kinase C; MHC, myosin heavy chain; NTG, nontransgenic; ANF, atrial netriuretic peptide.

	REFERENCES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				P. Penela, C. Murga, C. Ribas, A. S. Tutor, S. Peregrin, and F. Mayor Jr. Mechanisms of regulation of G protein-coupled receptor kinases (GRKs) and cardiovascular disease Cardiovasc Res, January 1, 2006; 69(1): 46 - 56. [Abstract] [Full Text] [PDF]

				G. Klein, A. Schaefer, D. Hilfiker-Kleiner, D. Oppermann, P. Shukla, A. Quint, E. Podewski, A. Hilfiker, F. Schroder, M. Leitges, et al. Increased Collagen Deposition and Diastolic Dysfunction but Preserved Myocardial Hypertrophy After Pressure Overload in Mice Lacking PKC{epsilon} Circ. Res., April 15, 2005; 96(7): 748 - 755. [Abstract] [Full Text] [PDF]

				G. E. Haddad, B. R. Coleman, A. Zhao, and K. N. Blackwell Regulation of atrial contraction by PKA and PKC during development and regression of eccentric cardiac hypertrophy Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H695 - H704. [Abstract] [Full Text] [PDF]

				C. M. Filipeanu, F. Zhou, W. C. Claycomb, and G. Wu Regulation of the Cell Surface Expression and Function of Angiotensin II Type 1 Receptor by Rab1-mediated Endoplasmic Reticulum-to-Golgi Transport in Cardiac Myocytes J. Biol. Chem., September 24, 2004; 279(39): 41077 - 41084. [Abstract] [Full Text] [PDF]

				V. U. Rao, H. Shiraishi, and P. J. McDermott PKC-{epsilon} regulation of extracellular signal-regulated kinase: a potential role in phenylephrine-induced cardiocyte growth Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2195 - H2203. [Abstract] [Full Text] [PDF]

				M. O. Gray, H.-Z. Zhou, I. Schafhalter-Zoppoth, P. Zhu, D. Mochly-Rosen, and R. O. Messing Preservation of Base-line Hemodynamic Function and Loss of Inducible Cardioprotection in Adult Mice Lacking Protein Kinase C{epsilon} J. Biol. Chem., January 30, 2004; 279(5): 3596 - 3604. [Abstract] [Full Text] [PDF]

				H. S. Hahn, Y. Marreez, A. Odley, A. Sterbling, M. G. Yussman, K. C. Hilty, I. Bodi, S. B. Liggett, A. Schwartz, and G. W. Dorn II Protein Kinase C{alpha} Negatively Regulates Systolic and Diastolic Function in Pathological Hypertrophy Circ. Res., November 28, 2003; 93(11): 1111 - 1119. [Abstract] [Full Text] [PDF]

				G. Wu, G. Zhao, and Y. He Distinct Pathways for the Trafficking of Angiotensin II and Adrenergic Receptors from the Endoplasmic Reticulum to the Cell Surface: Rab1-INDEPENDENT TRANSPORT OF A G PROTEIN-COUPLED RECEPTOR J. Biol. Chem., November 21, 2003; 278(47): 47062 - 47069. [Abstract] [Full Text] [PDF]

				E. M. Burkart, M. P. Sumandea, T. Kobayashi, M. Nili, A. F. Martin, E. Homsher, and R. J. Solaro Phosphorylation or Glutamic Acid Substitution at Protein Kinase C Sites on Cardiac Troponin I Differentially Depress Myofilament Tension and Shortening Velocity J. Biol. Chem., March 21, 2003; 278(13): 11265 - 11272. [Abstract] [Full Text] [PDF]

				E. A. Woodcock, B. H. Wang, J. F. Arthur, A. Lennard, S. J. Matkovich, X.-J. Du, J. H. Brown, and R. D. Hannan Inositol Polyphosphate 1-Phosphatase Is a Novel Antihypertrophic Factor J. Biol. Chem., June 14, 2002; 277(25): 22734 - 22742. [Abstract] [Full Text] [PDF]

				Y. Iijima, M. Laser, H. Shiraishi, C. D. Willey, B. Sundaravadivel, L. Xu, P. J. McDermott, and D. Kuppuswamy c-Raf/MEK/ERK Pathway Controls Protein Kinase C-mediated p70S6K Activation in Adult Cardiac Muscle Cells J. Biol. Chem., June 14, 2002; 277(25): 23065 - 23075. [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. J. ARONOW, T. TOYOKAWA, A. CANNING, K. HAGHIGHI, U. DELLING, E. KRANIAS, J. D. MOLKENTIN, and G. W. DORN II Divergent transcriptional responses to independent genetic causes of cardiac hypertrophy Physiol Genomics, June 6, 2001; 6(1): 19 - 28. [Abstract] [Full Text] [PDF]

				G. Wu, M. G. Yussman, T. J. Barrett, H. S. Hahn, H. Osinska, G. M. Hilliard, X. Wang, T. Toyokawa, A. Yatani, R. A. Lynch, et al. Increased Myocardial Rab GTPase Expression: A Consequence and Cause of Cardiomyopathy Circ. Res., December 7, 2001; 89(12): 1130 - 1137. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 275/39/29927    most recent C000380200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map