Protein Kinase C in Normal and Pathologic Myocardial States

Cain, Brian S.; Meldrum, Daniel R.; Harken, Alden H.

doi:10.1006/jsre.1998.5508

Cited by 16 publications

(8 citation statements)

References 99 publications

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“…This result is also in concert with animal and human data from our laboratory and others which have documented an inotropic response to exogenous Ca 2ϩ [10, 11, 13, 14, 23, 30 -33]. Mechanisms of Ca 2ϩ -induced inotropy have been previously discussed [14,15,23,34] and will not be further elaborated upon as they are not the primary finding of this report.…”

Section: Figsupporting

confidence: 90%

“…Mechanistic evaluation of cardiac preconditioning in the laboratory has revealed that ischemic stress seems to induce protection by various pathways which appear to act via adenosine-(ADO) [7], norepinephrine- [8,9], and calcium-(Ca 2ϩ ) [10 -14] mediated pathways in both animal and human myocardium. Further studies have revealed that these signaling mechanisms induce myocardial protection against ischemia mediated through protein kinase C (PKC) [15].…”

Section: Introductionmentioning

confidence: 99%

“…The myocardial ATP-sensitive K ϩ (KATP) channel is a putative end-effector of diverse preconditioning strategies [3] which serve to decrease ionic dyshomeostasis during/after ischemia-reperfusion (I/R) [15]. Gliben-clamide has been used experimentally to block the KATP channel and subsequent preconditioning in human myocardial tissues by transient ischemia (IPC) both in vivo [16] and in vitro [17] or by ADO pretreatment [7].…”

Section: Introductionmentioning

confidence: 99%

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Exogenous Calcium Preconditions Myocardium from Patients Taking Oral Sulfonylurea Agents

Cain

Meldrum

Meng

et al. 1999

Journal of Surgical Research

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Section: Figsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Exogenous Calcium Preconditions Myocardium from Patients Taking Oral Sulfonylurea Agents

Cain

Meldrum

Meng

et al. 1999

Journal of Surgical Research

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“…A role for PKC activation is implicated in the pathogenesis of cardiac hypertrophy, heart failure, and ischemic heart disease (32)(33)(34)(35). Genetic or pharmacologic inhibition of PKC activation improves cardiac contractility in several heart failure models (23,36,37).…”

Section: Discussionmentioning

confidence: 99%

PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1

Wang¹,

Kuyumcu‐Martinez²,

Sarma³

et al. 2009

J. Clin. Invest.

102

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Cardiac complications are a common cause of death in individuals with the inherited multisystemic disease myotonic dystrophy type 1 (DM1). A characteristic molecular feature of DM1 is misregulated alternative splicing due to disrupted functioning of the splicing regulators muscleblind-like 1 (MBNL1) and CUG-binding protein 1 (CUGBP1). CUGBP1 is upregulated in DM1 due to PKC pathway activation and subsequent CUGBP1 protein hyperphosphorylation and stabilization. Here, we blocked PKC activity in a heart-specific DM1 mouse model to determine its pathogenic role in DM1. Animals given PKC inhibitors exhibited substantially increased survival that correlated with reduced phosphorylation and decreased steady-state levels of CUGBP1. Functional studies demonstrated that PKC inhibition ameliorated the cardiac conduction defects and contraction abnormalities found in this mouse model. The inhibitor also reduced misregulation of splicing events regulated by CUGBP1 but not those regulated by MBNL1, suggesting distinct roles for these proteins in DM1 cardiac pathogenesis. The PKC inhibitor did not reduce mortality in transgenic mice with heart-specific CUGBP1 upregulation, indicating that PKC inhibition did not have a general protective effect on PKC-independent CUGBP1 increase. Our results suggest that pharmacological blockade of PKC activity mitigates the DM1 cardiac phenotype and provide strong evidence for a role for the PKC pathway in DM1 pathogenesis.

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“…Activation of PKC results in a wide range of effects, including compensated and decompensated myocardial hypertrophy, 37,38 as well as the cardioprotection of preconditioning. 39,40 Given the key role PKC occupies in the heart, manipulation of PKC activation might serve as a useful target for the management of myocardial dysfunction. However, the diverse nature of PKC requires that such treatment be specifically directed in order to minimize unintended effects.…”

Section: Discussionmentioning

confidence: 99%

Actin Capping Protein

Pyle

Hart

Cooper

et al. 2002

Circulation Research

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Abstract-Actin capping protein (CapZ) binds the barbed ends of actin at sarcomeric Z-lines. In addition to anchoring actin, Z-discs bind protein kinase C (PKC). Although CapZ is crucial for myofibrillogenesis, its role in muscle function and intracellular signaling is unknown. We hypothesized that CapZ downregulation would impair myocardial function and disrupt PKC-myofilament signaling by impairing PKC-Z-disc interaction. To test these hypotheses, we examined transgenic (TG) mice in which cardiac CapZ protein is reduced. Fiber bundles were dissected from papillary muscles and detergent extracted. Some fiber bundles were treated with PKC activators phenylephrine (PHE) or endothelin (ET) before detergent extraction. We simultaneously measured Ca 2ϩ -dependent tension and actomyosin MgATPase activity. CapZ downregulation increased myofilament Ca 2ϩ sensitivity without affecting maximum tension or actomyosin MgATPase activity. Maximum tension and actomyosin MgATPase activity were decreased after PHE or ET treatment of wild-type (WT) muscle. Fiber bundles from TG hearts did not respond to PHE or ET. Immunoblot analysis revealed an increase in myofilament-associated PKC-⑀ after PHE or ET exposure of WT preparations. In contrast, myofilamentassociated PKC-⑀ was decreased after PHE or ET treatment in TG myocardium. Protein levels of myofilamentassociated PKC-␤ were decreased in TG ventricle. C-protein and troponin I phosphorylation was increased after PHE or ET treatment in WT and TG hearts. Basal phosphorylation levels of C-protein and troponin I were higher in TG myocardium. These results indicate that downregulation of CapZ, or other changes associated with CapZ downregulation, increases cardiac myofilament Ca 2ϩ sensitivity, inhibits PKC-mediated control of myofilament activation, and decreases myofilament-associated PKC-␤.

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Protein Kinase C in Normal and Pathologic Myocardial States

Cited by 16 publications

References 99 publications

Exogenous Calcium Preconditions Myocardium from Patients Taking Oral Sulfonylurea Agents

Exogenous Calcium Preconditions Myocardium from Patients Taking Oral Sulfonylurea Agents

PKC inhibition ameliorates the cardiac phenotype in a mouse model of myotonic dystrophy type 1

Actin Capping Protein

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