Differential Induction of Protein Kinase C Isoforms at the Cardiac Hypertrophy Stage and Congestive Heart Failure Stage in Dahl Salt-Sensitive Rats

Koide, Yuichi; Tamura, Kouichi; Suzuki, Atsushi; Kitamura, K; Yokoyama, Keiko; Hashimoto, Tatsuo; Hirawa, Nobuhito; Kihara, Minoru; Ohno, Shigeo; Umemura, Satoshi

doi:10.1291/hypres.26.421

Cited by 39 publications

(23 citation statements)

References 50 publications

(60 reference statements)

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“…Since the cMyBPC phosphorylation status is affected by both PKA and PKC pathways, this change in phosphorylation may represent a net result of the differential influences of these kinases during the transition from adaptation to maladaptation. In addition, in some models of chronic pathologic hypertrophy, dilated cardiomyopathy, and heart failure (9,11,49), other PKC isoforms, such as PKCR and PKCδ, were also found to be upregulated. Whether or not the cMyBPC is also a substrate for these PKC isoforms is unknown.…”

Section: Discussionmentioning

confidence: 99%

PKCε Increases Phosphorylation of the Cardiac Myosin Binding Protein C at Serine 302 both in Vitro and in Vivo

Xiao

Zhao

et al. 2007

Biochemistry

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Cardiac myosin binding protein C (cMyBPC) phosphorylation is essential for normal cardiac function. Although PKC was reported to phosphorylate cMyBPC in vitro, the relevant PKC isoforms and functions of PKC-mediated cMyBPC phosphorylation are unknown. We recently reported that a transgenic mouse model with cardiac-specific overexpression of PKCepsilon (PKCepsilon TG) displayed enhanced sarcomeric protein phosphorylation and dilated cardiomyopathy. In the present study, we have investigated cMyBPC phosphorylation in PKCepsilon TG mice. Western blotting and two-dimensional gel electrophoresis demonstrated a significant increase in cMyBPC serine (Ser) phosphorylation in 12-month-old TG mice compared to wild type (WT). In vitro PKCepsilon treatment of myofibrils increased the level of cMyBPC Ser phosphorylation in WT mice to that in TG mice, whereas treatment of TG myofibrils with PKCepsilon showed only a minimal increase in cMyBPC Ser phosphorylation. Three peptide motifs of cMyBPC were identified as the potential PKCepsilon consensus sites including a 100% matched motif at Ser302 and two nearly matched motifs at Ser811 and Ser1203. We treated synthetic peptides corresponding to the sequences of these three motifs with PKCepsilon and determined phosphorylation by mass spectrometry and ELISA assay. PKCepsilon induced phosphorylation at the Ser302 site but not at the Ser811 or Ser1203 sites. A S302A point mutation in the Ser302 peptide abolished the PKCepsilon-dependent phosphorylation. Taken together, our data show that the Ser302 on mouse cMyBPC is a likely PKCepsilon phosphorylation site both in vivo and in vitro and may contribute to the dilated cardiomyopathy associated with increased PKCepsilon activity.

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Section: Discussionmentioning

confidence: 99%

PKCε Increases Phosphorylation of the Cardiac Myosin Binding Protein C at Serine 302 both in Vitro and in Vivo

Xiao

Zhao

et al. 2007

Biochemistry

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“…Prior studies have demonstrated the importance of apoptosis, caspases (Hayakawa et al, 2003;Chandrashekhar et al, 2004), and a variety of cellular pathways, including protein kinase C (PKC) activation (Takeishi et al, 1998;Koide et al, 2003) in the pathogenesis of CHF. There are also many studies demonstrating TUNEL positivity in a small (approximately 0.3%) population of cells in murine CHF models (Jiang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-Ribose) Polymerase Promotes Cardiac Remodeling, Contractile Failure, and Translocation of Apoptosis-Inducing Factor in a Murine Experimental Model of Aortic Banding and Heart Failure

Xiao

Chen

Zsengellér

et al. 2004

J Pharmacol Exp Ther

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Oxidant stress-induced activation of poly(ADP-ribose) polymerase (PARP) plays a role in the pathogenesis of various cardiovascular diseases. We have now investigated the role of PARP in the process of cardiac remodeling and heart failure in a mouse model of heart failure induced by transverse aortic constriction (banding). The catalytic activity of PARP was inhibited by the potent isoindolinone-based PARP inhibitor INO-1001 or by PARP-1 genetic deficiency. PARP inhibition prevented the pressure overload-induced decrease in cardiac contractile function, despite the pressure gradient between both carotid arteries being comparable in the two experimental groups. The development of hypertrophy, the formation of collagen in the hearts, and the mitochondrial-to-nuclear translocation of the cell death factor apoptosis-inducing factor (AIF) were attenuated by PARP inhibition. The ability of the inhibitor to block the catalytic activity of PARP was confirmed by immunohistochemical detection of poly(ADP-ribose), the product of the enzyme in the heart. Plasma levels of INO-1001, as measured at the end of the experiments, were in the concentration range sufficient to block the oxidant-mediated activation of PARP in murine cardiac myocytes in vitro. Myocardial hypertrophy and AIF translocation was also reduced in PARP-1-deficient mice undergoing aortic banding, compared with their wild-type counterparts. Overall, the current results demonstrate the importance of poly(ADP-ribos)ylation in the pathogenesis of banding-induced heart failure.Poly(ADP-ribose) polymerase (PARP)-1, a monomeric enzyme present in eukaryotes, is the major isoform of an expanding family of poly(ADP-ribosyl)ating enzymes (for review, see Virá g and Szabó, 2002). The main isoform of the family, PARP-1, primarily functions as a DNA damage sensor in the nucleus. Upon binding to damaged DNA mainly through the second zinc finger domain, PARP-1 forms homodimers and catalyzes the cleavage of NAD ϩ into nicotinamide and ADP-ribose and uses the latter to synthesize branched nucleic acid-like polymers poly(ADP-ribose) covalently attached to nuclear acceptor proteins. The biological role of PARP-1 is complex and includes the regulation of DNA repair and maintenance of genomic integrity.PARP-1 has been implicated in a variety of pathophysiological processes. PARP is an energy-consuming enzyme, which transfers ADP ribose units to nuclear proteins. As a result of this process, the intracellular nicotinamide dinucleotide (oxidized) (NAD ϩ ) and ATP levels remarkably decrease, resulting in cell dysfunction and cell death via the necrotic route (for review, see Virá g and Szabó, 2002).PARP becomes activated in response to DNA single-strand breaks, which can develop as a response to free radical and oxidant cell injury. Oxidative and nitrosative stress triggers the activation of the nuclear enzyme PARP, which contributes to the pathogenesis of various cardiovascular diseases, including myocardial infarction and ischemia-reperfusion and heart failure (for review, s...

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“…[13][14][15][16][17][18][19] We have previously shown that PKC␣ functions as a fundamental regulator of cardiac contractility and Ca 2ϩ handling in myocytes. 18,20 For example, PKC␣ gene-deleted mice were shown to be hypercontractile, whereas transgenic mice overexpressing PKC␣ were hypocontractile.…”

Section: Clinical Perspective P 582mentioning

confidence: 99%

Pharmacological- and Gene Therapy-Based Inhibition of Protein Kinase Cα/β Enhances Cardiac Contractility and Attenuates Heart Failure

et al. 2006

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Background-The conventional protein kinase C (PKC) isoform ␣ functions as a proximal regulator of Ca 2ϩ handling in cardiac myocytes. Deletion of PKC␣ in the mouse results in augmented sarcoplasmic reticulum Ca 2ϩ loading, enhanced Ca 2ϩ transients, and augmented contractility, whereas overexpression of PKC␣ in the heart blunts contractility. Mechanistically, PKC␣ directly regulates Ca 2ϩ handling by altering the phosphorylation status of inhibitor-1, which in turn suppresses protein phosphatase-1 activity, thus modulating phospholamban activity and secondarily, the sarcoplasmic reticulum Ca 2ϩ ATPase. Methods and Results-In the present study, we show that short-term inhibition of the conventional PKC isoforms with Ro-32-0432 or Ro-31-8220 significantly augmented cardiac contractility in vivo or in an isolated work-performing heart preparation in wild-type mice but not in PKC␣-deficient mice. Ro-32-0432 also increased cardiac contractility in 2 different models of heart failure in vivo. Short-term or long-term treatment with Ro-31-8220 in a mouse model of heart failure due to deletion of the muscle lim protein gene significantly augmented cardiac contractility and restored pump function. Moreover, adenovirus-mediated gene therapy with a dominant-negative PKC␣ cDNA rescued heart failure in a rat model of postinfarction cardiomyopathy. PKC␣ was also determined to be the dominant conventional PKC isoform expressed in the adult human heart, providing potential relevance of these findings to human pathophysiology. Conclusions-Pharmacological inhibition of PKC␣, or the conventional isoforms in general, may serve as a novel therapeutic strategy for enhancing cardiac contractility in certain stages of heart failure. (Circulation. 2006;114:574-582.)

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Differential Induction of Protein Kinase C Isoforms at the Cardiac Hypertrophy Stage and Congestive Heart Failure Stage in Dahl Salt-Sensitive Rats

Cited by 39 publications

References 50 publications

PKCε Increases Phosphorylation of the Cardiac Myosin Binding Protein C at Serine 302 both in Vitro and in Vivo

PKCε Increases Phosphorylation of the Cardiac Myosin Binding Protein C at Serine 302 both in Vitro and in Vivo

Poly(ADP-Ribose) Polymerase Promotes Cardiac Remodeling, Contractile Failure, and Translocation of Apoptosis-Inducing Factor in a Murine Experimental Model of Aortic Banding and Heart Failure

Pharmacological- and Gene Therapy-Based Inhibition of Protein Kinase Cα/β Enhances Cardiac Contractility and Attenuates Heart Failure

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