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Am J Physiol Heart Circ Physiol 293: H3768-H3771, 2007. First published October 5, 2007; doi:10.1152/ajpheart.00486.2007
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Inducible and myocyte-specific inhibition of PKC{alpha} enhances cardiac contractility and protects against infarction-induced heart failure

Michael Hambleton,1 Allen York,1 Michelle A. Sargent,1 Robert A. Kaiser,1 John N. Lorenz,2 Jeffrey Robbins,1 and Jeffery D. Molkentin1

1Department of Pediatrics, Cincinnati Children's Hospital Medical Center, and 2Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio

Submitted 23 April 2007 ; accepted in final form 1 October 2007


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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Mice null for the gene encoding protein kinase C{alpha} (Prkca), or mice treated with pharmacologic inhibitors of the PKC{alpha}/β/{gamma} isoforms, show an augmentation in cardiac contractility that appears to be cardioprotective. However, it remains uncertain if PKC{alpha} itself functions in a myocyte autonomous manner to affect cardioprotection in vivo. Here we generated cardiac myocyte-specific transgenic mice using a tetracycline-inducible system to permit controlled expression of dominant negative PKC{alpha} in the heart. Consistent with the proposed function of PKC{alpha}, induction of dominant negative PKC{alpha} expression in the adult heart enhanced baseline cardiac contractility. This increase in cardiac contractility was associated with a partial protection from long-term decompensation and secondary dilated cardiomyopathy after myocardial infarction injury. Similarly, Prkca null mice were also partially protected from infarction-induced heart failure, although the area of infarction injury was identical to controls. Thus, myocyte autonomous inhibition of PKC{alpha} protects the adult heart from decompensation and dilated cardiomyopathy after infarction injury in association with a primary enhancement in contractility.

protein kinase C; signaling; myocardial infarction

THE PROTEIN KINASE C (PKC) family of Ca2+ and/or lipid-activated serine-threonine kinases function downstream of many membrane-associated signal transduction pathways (4, 12). Approximately 10 different isozymes comprise the PKC family, which are broadly classified by their activation characteristics. The conventional PKC isozymes ({alpha}, βI, βII, and {gamma}) are Ca2+- and lipid-activated, while the novel isozymes ({varepsilon}, {theta}, {eta}, and {delta}) and atypical isozymes ({zeta} and {lambda}) are Ca2+ independent but activated by distinct lipids (4, 12). PKC{alpha} is the predominant PKC isoform expressed in the mouse, human, and rabbit heart, while PKCβ and PKC{gamma} are detectable and may have partially overlapping functions (7, 9, 10). With respect to the heart, a number of studies (4, 12) have associated PKC activation or an increase in PKC{alpha} expression with hypertrophy, dilated cardiomyopathy, ischemic injury, or mitogen stimulation.

We and others (1, 2, 5, 6) have shown that PKC{alpha} functions as a novel regulator of cardiac contractility through effects on Ca2+ handling and myofilament proteins. For example, Prkca (PKC{alpha}–/–) gene-deleted mice are hypercontractile, while transgenic mice overexpressing PKC{alpha} in the heart are hypocontractile. Enhancement in cardiac contractility associated with Prkca deletion protected against pressure overload-induced heart failure and dilated cardiomyopathy associated with deletion of the muscle lim protein (MLP) gene (Csrp3) in the mouse (2). More recently, we extended these results to include an analysis of pharmacologic inhibitors that are generally specific for the PKC{alpha}/β/{gamma} isoform subclass. Ro-32-0432 or Ro-31-8220 each significantly augmented cardiac contractility in vivo and in an isolated work performing heart preparation in wild-type (WT) mice but not in Prkca-deficient mice (7). While inhibition of PKC{alpha} would appear to be an attractive therapeutic approach for affecting heart disease, some areas of uncertainty remain. We addressed these uncertainties by 1) using a myocyte autonomous expression system for in vivo functional assessment, 2) using yet another model of heart failure associated with infarction injury, and 3) bypassing developmental compensatory issues by using an inducible system.


   MATERIALS AND METHODS
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 MATERIALS AND METHODS
RESULTS
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Animals. The Prkca null mice have been described previously (2). The rabbit dominant negative (dn) PKC{alpha} cDNA (–4–+2,647) with an L368A mutation was described previously (2). dnPKC{alpha} transgenic mice (FVBN strain) were generated by fusing dnPKC{alpha} cDNA, which was isolated and purified from the previously described rabbit adenoviral dnPKC{alpha}, to the cardiac-specific, inducible, and attenuated {alpha}-myosin heavy chain promoter ("responder" line) previously described (11). dnPKC{alpha} transgenic mice were bred with transcriptional transactivator ("driver" line) mice (11), which in the presense of doxycycline (Dox) administration inhibits all expression. Dox was removed at 4 wk of age, producing expression within another 8 wk (although expression was not immediate) at which time experiments were performed. Dox was administered in the food with a special diet formulated by Purina (625 mg/kg in pellets). Animal experiments were approved by the Institutional Animal Care and Use Committee.

Experimental design. Western blotting was performed as described previously with primary antibodies against PKC{alpha} (Santa Cruz Biotechnology; Ref. 2). Chemifluorescent detection was performed with the Vistra ECF reagent (Amersham Pharmacia Biotech) and scanned with a phosphorImager. For invasive hemodynamics in the closed-chest mouse, a 1.4 F Millar catheter was placed into the left ventricle through the right carotid artery to monitor real time heart rate, arterial and left ventricular pressures, and +dP/dt (dP/dtmax) and –dP/dt (dP/dtmin), using a PowerLab system and Chart software (AD Instruments, Colorado Springs, CO), as described previously (2). In this preparation, dobutamine was given at 32 µg·kg–1·min–1. The ischemia-reperfusion (IR) model was described previously (8), while the myocardial infarction (MI) injury model involved a similar procedure except that the left coronary artery (LCA) was permanently ligated in 12- to 14-wk-old mice (or a sham procedure for controls). For IR, a suture with a slipknot was tied around the LCA, and mice were revived for a 60-min ischemia period after which the knot was released and reperfusion in the heart occurred for 24 h. After reperfusion, mice were killed, the slipknot was retied, and hearts were analyzed as previously described using 2% triphenyltetrazolium chloride in saline. Myocardial area not at risk, area at risk, and infarcted area were quantified using ImageJ software (Scion, Frederick, MD). For echocardiography, all mice were anesthetized with isoflurane, and a Hewlett Packard 5500 instrument with a 15-MHz microprobe was used. Measurements were taken on M-mode in triplicate for the numbers indicated for each group. Mice were killed at 2 and 16 wk for analysis. Heart weight-to-body weight (HW/BW) ratios were recorded, and then the hearts were fixed in 10% formalin/PBS and embedded in paraffin and 8-µm heart sections were analyzed (8).

Statistical analysis. All data are means ± SE. Data were tested for significance with a one-way ANOVA followed by a Newman-Keuls posthoc test. For multiple groups, a two-way ANOVA was used followed by a pair-wise multigroup comparison by the Holm-Sidak method at each time point shown in GoFigs. 2A and B and 3A.


Figure 1
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  		Fig. 1. Induced expression of dominant negative (dn) PKC{alpha} in the adult heart augments contractility. A: diagram of promoter constructs used for the dual transgene tetracycline-inducible system based on the cardiac-specific {alpha}-myosin heavy chain (MHC) promoter. B: Western blot analysis of dnPKC{alpha} inducible expression in three transgenic lines that are double transgenic (DTG) with the transcriptional transactivator (tTA) transgene in the absence of doxycycline (Dox). Single dnPKC{alpha} transgenic mice show no expression, similar to wild type (WT). C: Western blot analysis examining PKC{alpha} expression in WT (lane 1), in dnPKC{alpha} single transgenic (lane 2), in DTG after Dox removal (lanes 3–5), in DTG born on Dox (lane 6), in DTG after Dox addition back to the diet (lane 7), and in negative and positive controls, respectively (lanes 8–9). D, E: invasive hemodynamics to assess cardiac function at baseline or after dobutamine β-agonist infusion in WT and DTG mice off (D) and on (E) Dox; numbers of animals are in bars. *P < 0.05 vs. WT.

 

Figure 2
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  		Fig. 2. dnPKC{alpha} expression partially protects from myocardial infarction (MI)-induced decompensation and remodeling. A: assessment of fractional shortening [FS=(LVED–LVES)/LVED*100, where LVED and LVES are left ventricular end-diastolic and end-systolic dimension, respectively] by echocardiography after MI or sham surgical procedure in DTG (n = 19–14; 8) after MI compared with WT mice after MI (n = 19–14; 7), along with WT (n = 12–11; 4) and DTG (n = 10–9; 4) sham groups. B: function in DTG (No Dox) mice compared with control groups on Dox after MI (no expression). The control groups were DTG MI (Dox) (n = 14–8; 4–3), WT MI (Dox) (n = 8–4; 4), and DTG (Dox) Sham (n = 6; 5–4). HW/BW ratios of WT and DTG (off Dox) 2 (C) or 16 wk (D) after MI or Sham. E: quantification of infarct area (IA) vs. area at risk (AAR) after ischemia-reperfusion injury in WT and DTG mice. [Note: some mice were killed at 2 and 16 wk. The first set of numbers in parenthesis (n) is the number of animals from wk 0–2, while the second set is the n after wk 2–16.] *P ≤ 0.05 vs. WT Sham; #P ≤ 0.05 vs. WT MI.

 

Figure 3
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  		Fig. 3. Prkca–/– mice are protected from MI-induced heart failure. A: assessment of fractional shortening in Prkca–/– mice (n = 18–14; 8–7) after MI compared with WT mice (n = 8–6; 5), along with WT (n = 8–6; 5) and Prkca–/– (n = 8; 4) sham groups. HW/BW ratios of WT and Prkca–/– mice 2 (B) and 16 (C) wk after MI or Sham. D: quantification of IA vs. AAR after ischemia-reperfusion injury in WT and Prkca–/– mice. Numbers of animals are in bars in B, C, and D. [Note: some mice were killed at 2 and 16 wk. The first set of numbers in parenthesis (n) is the number of animals from wk 0–2, while the second set is the n after wk 2–16.] *P ≤ 0.05 vs. WT Sham; ^P ≤ 0.05 vs. Prkca–/– Sham; #P ≤ 0.05 vs. WT MI.

 

   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
To examine more precisely the role of PKC{alpha} in regulating cardiac contractility and heart failure propensity, we generated myocyte-specific transgenic mice with inducible expression of a cDNA encoding dnPKC{alpha}. We used the newly reengineered bitransgenic tetracycline-regulated system that permits robust expression only when both transgenes are present in the absence of Dox (Fig. 1A; Ref. 11). Six dnPKC{alpha} transgenic lines were originally generated from which three lines were selected based on a lack of basal expression when crossed with the transcriptional transactivator "driver" transgene [making double transgenic mice (DTG)] in the presence of Dox but high levels of expression when Dox was removed (Fig. 1B). The dnPKC{alpha} protein migrates slightly faster on a Western blot because it is devoid of autophosphorylation. Line 10.11 was used for all subsequent analysis, as it appeared essentially the same as the other two lines. More careful characterization of this line showed no protein expression from the single transgene (Fig. 1C, lane 2) but good induction of dnPKC{alpha} in DTG mice in the absence of Dox (lanes 3, 4, and 5). Expression became gradually stronger over time as the Dox completely cleared the system of the animal (Fig. 1C). Importantly, when placed on Dox from birth or only for 3 days, DTG mice showed no dnPKC{alpha} expression (Fig. 1C, lanes 6 and 7). Consistent with Prkca–/– mice, adult DTG mice had increased contractility at baseline and with dobutamine infusion compared with wild type (WT), while DTG mice on Dox (no expression) did not have increased contractility compared with WT (Fig. 1, D and E). Dobutamine was used as a means of assessing the upper range of contractile responsiveness, which remained significantly greater in DTG mice.

To further examine the concept that subtle, albeit significant, increases in cardiac contractile performance can benefit the heart after pathologic stimulation, we performed MI injury in DTG mice. After MI, ventricular function assessed by echocardiography decreased within 1 wk in WT mice but was maintained in DTG mice. Fractional shortening (%) in DTG MI mice was significantly greater than in WT MI mice up to 3 wk after MI (Fig. 2A). As a control, DTG mice without Dox (induced) were compared with DTG mice on Dox (no expression), along with WT mice on Dox. DTG mice on Dox showed a significant reduction in functional performance after MI, similar to WT mice on Dox, yet DTG mice off Dox (induced) were partially protected at 1 and 2 wk after MI (Fig. 2B). However, by 12 and 16 wk after MI, even DTG mice off Dox (induced) showed signs of reduced ventricular performance that was similar to WT mice (see DISCUSSION).

Two weeks after MI injury all groups showed no significant increase in HW/BW ratios (Fig. 2C). However, by 16 wk WT mice had developed a significant increase in HW/BW, while the DTG mice did not (Fig. 2D). This partial protection from loss of ventricular performance and secondary increases in HW/BW ratios in DTG mice after MI was not due to less acute injury associated with PKC{alpha} inhibition, as WT mice had an equivalent IR injury response to DTG mice, and scar sizes were also equivalent at the end of the different experimental protocols (Fig. 2E, and data not shown). Finally, we have previously shown that PKC{alpha} does not directly regulate cardiac hypertrophy in mice (2); hence, we interpret the lack of hypertrophy at 16 wk in DTG mice to be associated with augmented function (see DISCUSSION).

The results presented with dnPKC{alpha} inducible transgenic mice were compared against Prkca–/– mice. As with DTG mice, ventricular function was maintained in Prkca–/– mice after MI compared with WT (Fig. 3A). Perhaps in an even more dramatic manner than the DTG mice, the fractional shortening (%) was rescued at most time points evaluated in Prkca–/– mice after MI compared with WT mice after MI (Fig. 3A). As with DTG mice, HW/BW ratios were not significantly altered at 2 wk after MI (Fig. 3B), but at 16 wk after MI, HW/BW ratios were increased in WT but not Prkca–/– mice (Fig. 3C). As with the DTG mice, Prkca–/– mice showed nearly identical infarction injuries as WT mice, as assessed by histological analysis and Masson's trichrome staining (data not shown). Similar to DTG mice, we also determined that loss of Prkca–/– did not alter the area of myocardial death within 24 h or IR injury compared with WT mice (Fig. 3D). These observations suggest that loss or inhibition of PKC{alpha} protects the heart in association with augmented contractile function.


   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The data presented here further strengthen the case for inhibiting PKC{alpha} as a therapeutic strategy for treating select forms of heart disease associated with reduced ventricular performance. Braz et al. (2) have previously shown that Prkca–/– mice were hypercontractile at baseline and partially protected from heart failure induced by long-term pressure overload or associated with loss of the Csrp3 gene (MLP). However, a significant concern with our previous data in Prkca–/– mice is that of developmental compensation, which often plagues gene-targeting experiments in the mouse. Also, loss of Prkca was not myocyte specific, so the effects in nonmyocytes (and tissues outside the heart) could have secondarily affected the contractile response in vivo. Despite these potential issues, acute inhibition of PKC{alpha} with the myocyte-specific inducible dominant negative transgene produced a very similar phenotype to the Prkca–/– mouse. Hambleton et al. (7) also previously used two distinct PKC inhibitory compounds in mice, resulting in an acute increase in cardiac contractility and a restoration of cardiac function in Crsp3 null mice. However, neither compound was completely selective for PKC{alpha}, so it was unclear as to which isoform was most important for inhibition. The use of dnPKC{alpha} affords greater specificity and was expressed at a more precise temporal moment, bypassing any potential compensatory effects by other genes. Another novel aspect of the current study was the examination of heart failure secondary to MI, which had not been previously analyzed.

Inhibition of PKC{alpha} with the dnPKC{alpha} only imparted a temporary increase in cardiac function within the first 1–3 wk after MI, while at later time points function deteriorated to levels that were more reminiscent of WT mice. However, Prkca–/– mice, which are maximally inhibited compared with only partial inhibition in dnPKC{alpha} mice, showed a better improvement in function after MI at nearly every time point up to 16 wk. This dramatic protection observed in the Prkca–/– mice reduced secondary hypertrophy by 16 wk of age, although even the partial protection observed in dnPKC{alpha} mice was sufficient to reduce the secondary hypertrophy response at 16 wk. The augmentation in ventricular performance after MI observed in either dnPKC{alpha} or Prkca–/– mice was not due to differences in the size of the initial infarction injury within the heart, suggesting that secondary remodeling was directly affected, potentially due to an intrinsic increase in contractility.

That augmentation in cardiac contractility can benefit an injured heart remains controversial. While traditional inotropes shorten life span in heart failure patients and putatively negative inotropic agents (β-adrenergic receptor blockers) extend life span, recent evidence in animal models of heart failure suggests that inotropic support, if properly targeted, can be of therapeutic value (3). The hypothesis put forth is that by selectively augmenting cardiac contractility in heart failure, function is restored above a threshold that abates neuroendocrine drive and the associated ventricular remodeling and progressive loss of myocytes from the heart (3). Inhibition of PKC{alpha} may be an ideal choice as a novel inotropic strategy, as it more directly targets calcium handling and possibly myofilament function without engaging upstream signaling pathways that typifies other inotropic strategies (1, 2).

While there is a clear need for novel inotropes to support late-stage heart failure patients in acute crisis, there may also be a therapeutic niche in earlier stages of heart failure if the inotrope is safe and not overly potent. Indeed, inhibition of PKC{alpha} may provide such an opportunity, as it appears to be a mild inotrope that is not subject to desensitization, and its mechanism of action at the level of the sarcoplasmic reticulum and myofilament proteins suggests that it could be safer than cAMP-elevating agents. However, it remains possible that inhibition of PKC{alpha} may also benefit the heart for reasons other than alterations in contractile performance, such as positively affecting ventricular remodeling and the activity of other stress signaling pathways. Either way, the data that have emerged in animal models suggest a number of therapeutic opportunities for focusing on PKC{alpha} as a heart failure target.


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This work was supported by grants from the National Institutes of Health (to J. Robbins and J. D. Molkentin), by an American Heart Association Established Investigator Grant (to J. D. Molkentin), and by the Fondation Leducq (Heart Failure Network Grant to J. D. Molkentin).


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. D. Molkentin, Division of Molecular Cardiovascular Biology, Dept. of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, Ohio 45229-3039 USA (e-mail: jeff.molkentin{at}cchmc.org)

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.


   REFERENCES
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
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  1. Belin RJ, Sumandea MP, Allen EJ, Schoenfelt K, Wang H, Solaro RJ, de Tombe PP. Augmented protein kinase C-alpha-induced myofilament protein phosphorylation contributes to myofilament dysfunction in experimental congestive heart failure. Circ Res 101: 195–204, 2007.[Abstract/Free Full Text]
  2. Braz JC, Gregory K, Pathak A, Zhao W, Sahin B, Klevitsky R, Kimball TF, Lorenz JN, Nairn AC, Liggett SB, Iodi B, Wang S, Schwartz A, Lakatta EG, DePaoli-Roach AA, Robbins J, Hewett TE, Bibb JA, Westfall MV, Kranias EG, Molkentin JD. PKC{alpha} regulates cardiac contractility and propensity towards heart failure. Nat Med 10: 248–254, 2004.[CrossRef][Web of Science][Medline]
  3. Dorn GW II, Molkentin JD. Manipulating cardiac contractility in heart failure: data from mice and men. Circulation 109: 150–158, 2004.[Free Full Text]
  4. Dorn GW II, Force T. Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest 115: 527–537, 2005.[CrossRef][Web of Science][Medline]
  5. El-Armouche A, Singh J, Naito H, Wittkopper K, Didie M, Laatsch A, Zimmermann WH, Eschenhagen T. Adenovirus-delivered short hairpin RNA targeting PKCalpha improves contractile function in reconstituted heart tissue. J Mol Cell Cardiol 43: 371–376, 2007.[CrossRef][Web of Science][Medline]
  6. Hahn HS, Marreez Y, Odley A, Sterbling A, Yussman MG, Hilty KC, Bodi I, Liggett SB, Schwartz A, Dorn GW II. Protein kinase Calpha negatively regulates systolic and diastolic function in pathological hypertrophy. Circ Res 93: 1111–1119, 2003.[Abstract/Free Full Text]
  7. Hambleton M, Hahn H, Pleger ST, Kuhn MC, Klevitsky R, Carr AN, Kimball TF, Hewett TE, Dorn 2nd GW, Koch WJ, Molkentin JD. Pharmacological- and gene therapy-based inhibition of protein kinase Calpha/beta enhances cardiac contractility and attenuates heart failure. Circulation 114: 574–582, 2006.[Abstract/Free Full Text]
  8. Kaiser RA, Liang Q, Bueno O, Huang Y, Lackey T, Klevitsky R, Hewett TE, Molkentin JD. Genetic inhibition or activation of JNK1/2 protects the myocardium from ischemia-reperfusion-induced cell death in vivo. J Biol Chem 280: 32602–32608, 2005.[Abstract/Free Full Text]
  9. Pass JM, Gao J, Jones WK, Wead WB, Wu X, Zhang J, Baines CP, Bolli R, Zheng YT, Joshua IG, Ping P. Enhanced PKC beta II translocation and PKC beta II-RACK1 interactions in PKC epsilon-induced heart failure: a role for RACK1. Am J Physiol Heart Circ Physiol 281: H2500–H2510, 2001.[Abstract/Free Full Text]
  10. Ping P, Zhang J, Qiu Y, Tang XL, Manchikalapudi S, Cao X, Bolli R. Ischemic preconditioning induces selective translocation of protein kinase C isoforms epsilon and eta in the heart of conscious rabbits without subcellular redistribution of total protein kinase C activity. Circ Res 81: 404–414, 1997.[Abstract/Free Full Text]
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