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(Circulation Research. 2000;86:1218.)
© 2000 American Heart Association, Inc.

Integrative Physiology

Transgenic Overexpression of Constitutively Active Protein Kinase C Causes Concentric Cardiac Hypertrophy

Yasuchika Takeishi, Peipei Ping, Roberto Bolli, Darryl L. Kirkpatrick, Brian D. Hoit, Richard A. Walsh

From the Department of Medicine (Y.T., D.L.K., B.D.H., R.A.W.), Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, and Experimental Research Laboratory, Division of Cardiology (P.P., R.B.), University of Louisville, Louisville, Ky.

Correspondence to Richard A. Walsh, MD, Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland, 11100 Euclid Ave, Lakeside Room 3563, Cleveland, OH 44106-5029. E-mail raw19{at}po.cwru.edu

	Abstract

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Abstract—To test the hypothesis that activation of the protein kinase C (PKC) isoform leads to cardiac hypertrophy without failure, we studied transgenic mice with cardiac-specific overexpression of a constitutively active mutant of the PKC isoform driven by an –myosin heavy chain promoter. In transgenic mice, the protein level of PKC in heart tissue was increased 9-fold. There was a 6-fold increase of the membrane/cytosol ratio, and PKC activity in the membrane fraction was 4.2-fold compared with wild-type mice. The heart weight was increased by 28%, and upregulation of the mRNA for ß-myosin heavy chain and -skeletal actin was observed in transgenic mouse hearts. Echocardiography demonstrated increased anterior and posterior wall thickness with normal left ventricular function and dimensions, indicating concentric cardiac hypertrophy. Isolated cardiomyocyte mechanical function was slightly decreased, and Ca²⁺ signals were markedly depressed in transgenic mice, suggesting that myofilament sensitivity to Ca²⁺ was increased. No differences were observed in either the levels of cardiac Ca²⁺-handling proteins or the degree of cardiac regulatory protein phosphorylation between wild-type and transgenic mice. Unlike mice with PKCß₂ overexpression, transgenic mice with cardiac-specific overexpression of the active PKC mutant demonstrated concentric hypertrophy with normal in vivo cardiac function. Thus, PKC isoforms may play differential functional roles in cardiac hypertrophy and failure.

Key Words: hypertrophy • signal transduction • transgenic mouse • heart failure • protein kinase C

	Introduction

Top Abstract Introduction Materials and Methods Results Discussion References

 
Activation of the protein kinase C (PKC) signaling pathway has been implicated in the development of cardiomyocyte hypertrophy.^{1 2} Currently, at least 11 isoforms of this family of serine/threonine kinases have been identified, and their expression in the heart is developmentally regulated.³ Although PKC isoforms may play different functional roles in cell signaling, the exact significance of individual isoforms is not yet known. We have reported in the failing human myocardium with end-stage heart failure that the expression and activity of Ca²⁺-sensitive PKC and -ß isoforms are elevated.⁴ In isolated guinea pig hearts, oxidative stress using H₂O₂ induces left ventricular dysfunction associated with translocation of Ca²⁺-sensitive PKC isoforms.⁵ We have also demonstrated that postnatal cardiac-specific overexpression of the PKCß₂ isoform in transgenic mice causes a cardiomyopathy that is characterized by left ventricular hypertrophy, myocardial fibrosis, and decreased in vivo left ventricular performance.⁶ In these mice, PKCß₂-induced phosphorylation of the myofilament regulatory protein troponin I decreases cardiomyocyte Ca²⁺ sensitivity and may cause the depressed cardiomyocyte function.⁷ These observations have suggested a critical role of the PKCß isoform in the genesis of contractile dysfunction.

On the other hand, the Ca²⁺-independent PKC isoform has been implicated in cardiac hypertrophy and ischemic preconditioning.^{8 9} An in vitro study using neonatal cardiomyocytes has shown that PKC, but not tyrosine kinase or Ras, is critical for angiotensin II–induced activation of extracellular signal–regulated kinase (ERK), which promotes cardiac hypertrophy by activating transcription factors.¹⁰ Among PKC isoforms, PKC, but not PKC, is a mediator for ERK activation induced by endothelin-1 and phenylephrine.¹¹ Moreover, we have demonstrated in the isolated adult guinea pig heart that pathophysiologic elevation of left ventricular diastolic pressure activates phospholipase C and accumulates inositol phosphate with resultant translocation of the PKC isoform.¹² This PKC translocation by mechanical stretch is attenuated by an AT₁ antagonist. In addition, we have shown that the PKC isoform is essential for ERK activation in in vitro rabbit cardiomyocytes¹³ and in vivo mouse hearts.¹⁴ Interestingly, activation of PKC is not observed in explanted myocardial tissue from patients with end-stage heart failure.⁴ On the basis of these findings, we hypothesized that activation of the PKC isoform may lead to compensated ventricular hypertrophy. To test this hypothesis, we generated transgenic mice with cardiac-specific overexpression of a constitutively active mutant of the PKC isoform using an –myosin heavy chain (MHC) promoter. Cardiac-specific PKC transgenesis made possible an in vivo evaluation of PKC-mediated signaling pathways on cardiac hypertrophy and function without interference from phosphorylation events mediated either by other PKC isoforms or by upstream Gq.

	Materials and Methods

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All procedures were performed in accordance with Case Western Reserve University animal care guidelines, which conform with the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health.

Production of PKC Transgenic Mice
PKC transgenic mice were generated by P.P. and R.B.¹⁴ Briefly, a full-length PKC cDNA was cloned from a rabbit heart cDNA library. Because the majority of the wild-type PKC isoform resides in the cytosolic fraction and is usually self-inhibited, transgenesis with the wild-type PKC may not lead to effective substrate phosphorylation in the membrane-particulate fraction. Thus, a constitutively active PKC cDNA was generated through a mutation by converting A to E (amino acid 159) as previously described.^{13 14} This mutation prevents the pseudosubstrate domain from binding to the catalytic domain, and thus renders the molecule active. A linear 11.4-kb DNA fragment containing the entire -MHC promoter (a gift from J. Robbins, Children’s Hospital Research Foundation, Cincinnati, Ohio), the complete PKC cDNA with the mutation, and a polyadenylation signal was released by digestion with NotI and was used for microinjection into pronuclei of fertilized FVB mouse eggs as previously reported.^{6 15 16 17} The presence of the transgene was screened by Southern analysis of genomic DNA extracted from mouse tail using a ³²P-labeled 1.9-kb EcoRI fragment as a probe.

Northern Blotting
The total RNA (10 µg/lane) was extracted from mouse hearts and hybridized under conditions previously described^{6 15 16 17} using a ³²P-labeled BamHI-SalI fragment as a probe. Quantitative assessment of cardiac hypertrophic gene expression was performed using gene-specific oligonucleotides (gifts from G.J. Babu and M. Periasamy, University of Cincinnati) as previously described.^{6 16}

Quantitative Immunoblotting
Quantitative immunoblotting of cardiac homogenates was used to determine the levels of PKC and Ca²⁺ handling proteins as previously described.^{4 5 6 7}

PKC Activity
The isoform-selective PKC phosphorylation activity in the myocardium was measured as previously described.^{4 6 8} Briefly, proteins were immunoprecipitated with PKC-specific antibody, and the activity was defined as phosphatidylserine- and phorbol 12-myristate 13-acetate–stimulated transfer of ³²P from [-³²P]ATP into the PKC-specific substrate (ERMRPRKRQGSVRRRV).

Echocardiography
Mice were anesthetized with tribromoethanol, and cardiac ultrasound studies were performed with an Acuson Sequoia ultrasonograph equipped with a 15-MHz linear array imaging transducer as previously reported.^{6 15}

Isolated Cardiomyocyte Mechanical Properties and Ca²⁺ Signals
Left ventricular cardiomyocytes were isolated from mouse hearts, and cardiomyocyte mechanical properties were examined, as we previously described.^{7 15 17} Half of the isolated cells were used for measurements of cytosolic free Ca²⁺ by ratio imaging of fura-2 fluorescence, as reported previously.^{7 15 17} Eight to ten cardiomyocytes were analyzed for each mouse, and statistical analyses were performed on the basis of the number of hearts studied.

Phosphorylation of Membranous and Myofibrillar Proteins
Isolated cardiomyocytes were incubated with [³²P]orthophosphate as previously described.^{7 18} PAGE of ³²P_i-labeled proteins was performed using 4% to 20% gradient SDS gels, and ³²P_i-labeled proteins were identified using a phosphor imager and autoradiography.

Statistics
Statistical analysis was done with unpaired t tests. If data were not normally distributed or failed equal variance tests after log₁₀ transformations, they were analyzed by nonparametric statistics (Mann-Whitney rank sum test). A P value of <0.05 was considered significant.

	Results

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Transgenic mice 9 to 12 weeks of age and age-matched wild-type littermate control mice were used for the present study. A transgenic line expressing intermediate levels of the transgene (No. 388) was chosen for detailed characterization. Northern blot analysis revealed that the PKC mRNA level in transgenic hearts was 15-fold in this line. Immunoblot analysis performed with specific antibodies for PKC showed that the protein levels of the PKC isoform in the heart were increased by 9-fold in the transgenic mice compared with the wild-type mice (Figure 1A). As shown in Figure 1B, the membrane-particulate/cytosol ratio of PKC was 0.56±0.21 in wild-type mice and 3.04±0.44 in transgenic mice (n=4, P<0.01). PKC activity in membrane-particulate and cytosolic fractions were 4.2±0.3-fold and 1.6±0.1-fold compared with wild-type controls (n=5, P<0.01), respectively. The PKC transgenesis did not alter the expression and subcellular distribution of any of the other PKC isoforms expressed in the mouse heart (, ß₂, , , , and ). Immunoblots of PKC are shown in Figure 1C as an example. The protein expressions of the PKC isoform in lungs, liver, kidney, large intestine, and small intestine were similar between wild-type and transgenic mice (data not shown). Systolic blood pressure of 3 transgenic and 3 wild-type littermate mice was measured with the mice in the conscious state using the standard tail cuff method in a blinded fashion. There were no differences in systolic blood pressure between transgenic and wild-type mice (136±9 versus 139±11 mm Hg, respectively).

View larger version (30K): [in this window] [in a new window]   Figure 1. A, Representative immunoblots of the PKC isoform in whole cardiac homogenates from wild-type (WT) and transgenic (TG) mice. B, PKC immunoblots in purified membrane-particulate (M) and cytosolic (C) fractions. C, Same membrane as in Figure 1B was reprobed with anti-PKC antibody. PKC transgenesis did not change subcellular distribution of PKC.

Heart Weight and Lung Weight
The gravimetric data of wild-type littermate and PKC transgenic mice are summarized in Table 1. The absolute heart weight and ratio of heart to body weight were increased in transgenic mice compared with wild-type mice by 28% and 21%, respectively. The lung weight and ratio of lung to body weight were the same between the wild-type and transgenic mice. There was no evidence of fibrosis on microscopic examinations of multiple histological sections from transgenic mouse hearts (data not shown).

View this table: [in this window] [in a new window]   Table 1. Heart Weight and Lung Weight of Wild-Type and PKC-Overexpressing Transgenic Mice

Expression of Hypertrophic Genes
Quantitative assessment of cardiac hypertrophic gene expression, such as atrial natriuretic factor (ANF), c-fos, ß-MHC, and -skeletal actin, was performed by Northern blot analysis. Representative Northern blots and quantitative data are shown in Figure 2. Each value was normalized to the mRNA expression of GAPDH. Increased transcript levels of ß-MHC (4-fold) and -skeletal actin (7-fold) were observed in transgenic mouse hearts without significant changes in levels of ANF and c-fos.

View larger version (24K): [in this window] [in a new window]   Figure 2. A, Representative Northern blots of ANF, c-fos, ß-MHC, -skeletal actin (Sk Actin), and GAPDH in wild-type (WT) and transgenic (TG) mice. B, Quantitative group data analysis of mRNA expression normalized to GAPDH expression from 3 wild-type and 4 transgenic mice. **P<0.01.

Echocardiography
M-mode echocardiographic measurements include the left ventricular minor axis dimension at end-diastole (EDD) and end-systole (ESD) and wall thickness at end-diastole of the anterior (AWTh) and posterior (PWTh) walls. Representative M-mode echocardiograms from a wild-type mouse and a transgenic mouse are shown in Figure 3A, and group data of echocardiographic measurements are summarized in Table 2. There were no differences in EDD, ESD, and fractional shortening between wild-type and transgenic mice. In contrast, the AWTh, PWTh, and left ventricular mass were increased in transgenic mice compared with wild-type mice. The relative wall thickness was higher in transgenic mice than in wild-type mice, indicating the presence of concentric hypertrophy in PKC transgenic hearts.

View larger version (35K): [in this window] [in a new window]   Figure 3. A, Representative M-mode echocardiograms of a wild-type mouse and a transgenic mouse. EDD indicates end-diastolic dimension; ESD, end-systolic dimension. B, Representative analog recordings of cardiomyocyte mechanics and Ca2+ transients of cells isolated from a wild-type littermate and a PKC transgenic mouse. C, Autoradiograms of SDS polyacrylamide gels (4 to 20% gradient) for transgenic (TG) and wild-type (WT) mice. Phosphorylated bands were identified on the basis of their migration patterns relative to pure protein standards as reported previously.7 19 Troponin I was identified by stimulation of phosphorylation with dibutyryl cAMP. Phospholamban was identified by its characteristic mobility shift on boiling before electrophoresis.

View this table: [in this window] [in a new window]   Table 2. Echocardiographic Data

Isolated Cardiomyocyte Mechanical Function and Ca²⁺ Transients
Representative analog recordings of isolated left ventricular cardiomyocyte mechanics and Ca²⁺ transients for wild-type and PKC transgenic mice are shown in Figure 3B. Group data for the cardiomyocyte mechanical properties and Ca²⁺ transients are summarized in Table 3. The percentage of cardiomyocyte shortening (P<0.05) was slightly decreased in PKC transgenic mice compared with wild-type control mice. The baseline Ca²⁺ level was slightly lower, and the amplitude of the Ca²⁺ transient was markedly decreased in transgenic mice compared with wild-type mice (P<0.01). The times from start to 80% decay of the Ca²⁺ signal (T₈₀) and 50% decay of the Ca²⁺ signal (T₅₀) were prolonged in transgenic mice. The observed disparities between cardiomyocyte mechanics and Ca²⁺ transient data suggested that myofilament sensitivity to Ca²⁺ was relatively increased in transgenic mouse hearts.

View this table: [in this window] [in a new window]   Table 3. Mechanical Properties and Calcium Transients of Isolated Left Ventricular Cardiomyocytes

Protein Levels Involved in Ca²⁺ Homeostasis
To determine whether the observed changes in the cardiomyocyte Ca²⁺ signal were associated with altered expression of Ca²⁺-handling proteins, the relative levels of these proteins in the heart were determined by quantitative immunoblotting (Table 4). No significant differences in phospholamban, sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2a), the Na⁺-Ca²⁺ exchanger, or the Na⁺-H⁺ exchanger were found between PKC transgenic and wild-type mice.

View this table: [in this window] [in a new window]   Table 4. Protein Abundance of Cardiac Calcium Handling Proteins

Phosphorylation of Cardiac Proteins
To clarify whether the suspected changes in myofilament Ca²⁺ sensitivity were associated with altered phosphorylation status of cardiac regulatory proteins, we examined the degree of cardiac protein phosphorylation. The incorporation of [³²P]orthophosphate into a variety of cardiac proteins was studied in cardiomyocytes isolated from wild-type and transgenic mice hearts. The degree of protein phosphorylation at basal condition was expressed as a percentage of that after maximal stimulation with dibutyryl cAMP. As shown in Figure 3C and Table 5, no differences were found in the degree of phosphorylation of troponin I, troponin T, phospholamban, and 15-kDa protein between wild-type and transgenic mice.

View this table: [in this window] [in a new window]   Table 5. 2P Incorporation Into Cardiac Membranous and Myofibrillar Proteins

	Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
The major findings of the present study were as follows: transgenic mice with cardiac-specific overexpression of a constitutively active mutant of PKC demonstrated (1) 4.2-fold increase of PKC activity in the membrane fraction; (2) mild concentric hypertrophy; (3) no evidence of fibrosis; (4) normal in vivo left ventricular performance; (5) slightly decreased isolated cardiomyocyte function and markedly depressed Ca²⁺ transients, suggesting an increase in myofilament Ca²⁺ sensitivity; (6) partial recapitulation of fetal gene expression; (7) unchanged abundance of Ca²⁺ cycling proteins; and (8) no differences in the degree of cardiac myofilament or sarcoplasmic reticulum regulatory protein phosphorylation.

Differential Roles of PKC Isoforms in Cardiac Hypertrophy and Failure
The phenotype resulting from postnatal cardiac overexpression of PKC differs considerably from that observed in transgenic mice overexpressing PKCß₂. These mice, which had a comparable level of PKC activity (5-fold in membrane fraction), demonstrated a heart failure phenotype^{6 7} that was characterized by (1) in vivo systolic dysfunction by echocardiography, (2) decreased isolated cardiomyocyte function and normal Ca²⁺ kinetics, and (3) decreased myofilament responsiveness to Ca²⁺ resulting from increased phosphorylation of troponin I. Taken together, these data suggest differential functional roles for distinct PKC isoforms and support the notion that increased activity of PKCß, but not PKC, could depress contractile function in heart failure. However, in a separate study, a transgenic line with an extraordinarily high level of constitutively active PKC (34-fold in protein level), demonstrated a heart failure phenotype.¹⁹ Whether this represents a "dose effect" from excessive PKC gene expression, a nonspecific effect of very high levels of cardiomyocyte protein loading, or an insertional effect of the transgene is unclear at this time.

Despite normal in vivo cardiac performance by echocardiography, isolated cardiomyocyte mechanical function was modestly reduced in transgenic mice compared with wild-type control (9.6% versus 11.8%). This discordance might be explained by differences in experimental conditions such as partial contracture after enzymatic myocyte extraction, which has been observed in this and other studies.^{7 20} In addition, compensatory alterations in chamber geometry (concentric hypertrophy) and reflex control of the circulation may affect in vivo systolic left ventricular performance.

A preliminary echocardiographic study in a small number of retired breeders demonstrated that fractional shortening in 48-week-old transgenic mice was depressed compared with age-matched wild-type littermate controls. These data suggest that PKC mice may develop an age-related impairment of systolic function, similar to that observed in other transgenic models.²¹

Although ANF is thought to be a marker of hypertrophy, the mRNA level of ANF was unexpectedly unchanged in PKC transgenic mouse hearts in the present study. However, it should be recognized that hypertrophy may not always be associated with increased ventricular expression of ANF.²²

Possible Mechanisms for Decreased Cardiomyocyte Ca²⁺ Transients
Although the amplitude of Ca²⁺ signals of isolated cardiomyocytes was decreased in transgenic mice compared with wild-type mice, the levels of Ca²⁺ handling proteins such as SERCA2a, phospholamban, the Na⁺-Ca²⁺ exchanger, and the Na⁺-H⁺ exchanger were similar between wild-type and transgenic mice. We cannot exclude the possibility that changes in the intrinsic activities of these proteins may account for the depressed Ca²⁺ amplitude in transgenic mouse hearts. Other possible mechanisms for reduced Ca²⁺ signals include (1) altered biophysical environment of the sarcoplasmic reticulum²³ ; (2) altered spatial coupling between voltage-gated Ca²⁺ channels and the ryanodine receptor²⁴ ; and (3) altered activity and abundance of other Ca²⁺-dependent phospholipid binding proteins such as annexins. For example, it has been demonstrated that transgenic overexpression of annexin VI in mice resulted in decreased basal and peak Ca²⁺ transients.²⁰

Alterations in Myofilament Ca²⁺ Sensitivity
It is well known that altered Ca²⁺ kinetics modify cardiac contractility.¹ Although the amplitude of Ca²⁺ signals of isolated cardiomyocytes was depressed in transgenic mice (53% of wild type), isolated cardiomyocyte function was relatively preserved (81% of wild type), and in vivo cardiac function assessed by echocardiography was normal in these transgenic mice. These findings suggest that increased myofilament Ca²⁺ sensitivity may contribute to the preserved left ventricular chamber and cardiomyocyte function that we observed. This compensatory mechanism would offset the functional results of diminished cellular Ca²⁺ handling.

The mechanisms by which myofibrillar Ca²⁺ sensitivity may be altered include (1) phosphorylation of myofibrillar proteins,²⁵ (2) changes in regulatory contractile protein isoforms,²⁶ and (3) regulation of intracellular pH.²⁷ It has been reported that phosphorylation of troponin I or T by PKC reduces Ca²⁺ sensitivity and maximal activity of actomyosin MgATPase and thus impairs actin-myosin interactions.²⁸ However, in the present study, unlike in mice with PKCß₂ overexpression, the degree of phosphorylation of both troponin I and T was unchanged in PKC transgenic hearts. Phosphorylation specificities of PKC isoforms for cardiac regulatory proteins have been reported in in vitro studies.²⁹ PKC phosphorylates Ser43/Ser45 of troponin I and reduces Ca²⁺ sensitivity and maximal activity of MgATPase. In contrast, PKC phosphorylates 2 unknown sites of troponin T and results in a slight increase of Ca²⁺ sensitivity. PKC can potentially modify the regulation of intracellular pH through the activation of the Na⁺-H⁺ exchanger and secondarily alter myofibrillar Ca²⁺ sensitivity.³⁰ However, we did not find a change in the protein level of the Na⁺-H⁺ exchanger in the present study. It is possible that changes in intracellular pH mediated by PKC-induced phosphorylation and resultant activation of the Na⁺-H⁺ exchanger might contribute, at least in part, to an increase in myofilament sensitivity to Ca²⁺ observed in the present study. We are currently examining this possibility.

Conclusion
Cardiac-specific overexpression of a constitutively active mutant of PKC causes mild concentric hypertrophy with normal in vivo cardiac performance. These and other data from our laboratory support the notion that activation of Ca²⁺-sensitive PKC isoforms, but not the PKC isoform, predominates in mediating contractile dysfunction of failing myocardium. Furthermore, they suggest that distinct PKC isoforms may play differential functional roles in cell signaling pathways leading to cardiac hypertrophy and failure.

	Acknowledgments

 
This work was supported in part by grants from NIH (HL-52318 to R.A.W., HL-58166 to P.P., and HL-43151 and HL-55757 to R.B.), the American Heart Association (9750721N to P.P. and 9650695N to B.D.H.), and the Japanese Heart Foundation (to Y.T.).

	Footnotes

 
This manuscript was sent to Stephen F. Vatner, Consulting Editor, for review by expert referees, editorial decision, and final disposition.

Received February 8, 2000; accepted April 28, 2000.

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