A mitogen-activated protein kinase is involved in the inotropic but not chronotropic actions of adrenoceptor agonists and endothelin-1

Peters, Stephan L. M.; Sand, Carsten; Michel, Martin C.; Pfaffendorf, M.; Zwieten, P. A. van

doi:10.1007/s00210-002-0573-7

Cited by 8 publications

(6 citation statements)

References 14 publications

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“…The addition of bis-1, a PKC antagonist, largely inhibited the functional effects of ET-1, suggesting that PKC was a key contributor to cTnI phosphorylation in response to ET-1. MAPKs can act as downstream effectors of activated PKC, and each pathway influences cardiac contractile function (133,411,491,684), but MAPK inhibitors did not significantly influence acute ET-1-mediated cTnI phosphorylation. The PKA inhibitor H-89 did not significantly influence cTnI phosphorylation in response to ET-1 (266).…”

Section: Downstream Translocation and Other Signaling Pathwaysmentioning

confidence: 98%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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The birth of molecular cardiology can be traced to the development and implementation of high-fidelity genetic approaches for manipulating the heart. Recombinant viral vector-based technology offers a highly effective approach to genetically engineer cardiac muscle in vitro and in vivo. This review highlights discoveries made in cardiac muscle physiology through the use of targeted viral-mediated genetic modification. Here the history of cardiac gene transfer technology and the strengths and limitations of viral and nonviral vectors for gene delivery are reviewed. A comprehensive account is given of the application of gene transfer technology for studying key cardiac muscle targets including Ca2+handling, the sarcomere, the cytoskeleton, and signaling molecules and their posttranslational modifications. The primary objective of this review is to provide a thorough analysis of gene transfer studies for understanding cardiac physiology in health and disease. By comparing results obtained from gene transfer with those obtained from transgenesis and biophysical and biochemical methodologies, this review provides a global view of cardiac structure-function with an eye towards future areas of research. The data presented here serve as a basis for discovery of new therapeutic targets for remediation of acquired and inherited cardiac diseases.

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Section: Downstream Translocation and Other Signaling Pathwaysmentioning

confidence: 98%

Designing Heart Performance by Gene Transfer

Davis¹,

Westfall²,

Townsend³

et al. 2008

Physiological Reviews

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show abstract

“…The PKC pathway was primarily responsible for phosphorylation of cTnI in response to ET, as indicated by the reduction of cTnI phosphorylation to basal levels in myocytes treated with bis-1 or chelerythrine ( Activation of the ERK1/2, JNK, and p38 pathways were examined because each of these MAPKs can act as downstream effectors of activated PKC, and each pathway influences cardiac contractile function (23,(41)(42)(43)). An inhibitor of protein kinase A, H-89 (13) also did not significantly influence cTnI phosphorylation in response to ET (results not shown).…”

Section: Basal and Agonist-mediated Tni Phosphorylation By Pkc Inmentioning

confidence: 99%

Role of Troponin I Phosphorylation in Protein Kinase C-mediated Enhanced Contractile Performance of Rat Myocytes

Westfall

Borton²

2003

Journal of Biological Chemistry

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Our goal was to define the role of phosphorylated cardiac troponin-I in the adult myocyte contractile performance response to activated protein kinase C. In agreement with earlier work, endothelin enhanced both adult rat myocyte contractile performance and cardiac troponin-I phosphorylation. Protein kinase C participated in both responses. The role of cardiac troponin-I phosphorylation in the contractile function response to protein kinase C was further investigated using gene transfer into myocytes of troponin-I isoforms/mutants lacking one or more phosphorylation sites previously identified in purified cardiac troponin-I. Sarcomeric replacement with slow skeletal troponin-I-abrogated protein kinase C-mediated troponin-I phosphorylation. In functional studies, endothelin slowed relaxation in myocytes expressing slow skeletal troponin-I, while the relaxation rate increased in myocytes expressing cardiac troponin-I. Based on these results, acceleration of myocyte relaxation during protein kinase C activation largely depended on cardiac troponin-I phosphorylation. Experiments with troponin-I isoform chimeras provided evidence that phosphorylation sites in the amino portion of cardiac troponin I-mediated the protein kinase C acceleration of relaxation. The cardiac troponin-I Thr-144 phosphorylation site identified in earlier biochemical studies was not significantly phosphorylated during the acute contractile response. Thus, aminoterminal protein kinase C-dependent phosphorylation sites in cardiac troponin-I are likely responsible for the accelerated relaxation observed in adult myocytes. Troponin I (TnI)1 is a key regulatory protein within the thin filament of the contractile apparatus. Different isoforms of TnI influence myofilament Ca 2ϩ sensitivity (1) and contribute to developmental changes in myofilament function. In particular, the transition from slow skeletal TnI (ssTnI) expression in embryonic/fetal hearts to the cardiac isoform expressed exclusively in adult hearts appears to "fine tune" myofilament regulatory function (1, 2). The Ca 2ϩ sensitivity properties of the myofilaments also can be modified by TnI phosphorylation (3). For example, ␤-adrenergic activation of protein kinase A (PKA) phosphorylates cardiac TnI (cTnI), which reduces myofilament Ca 2ϩ sensitivity (3) and contributes to accelerated relaxation in intact adult myocardium (4). TnI also is phosphorylated by activated protein kinase C (PKC) (5, 6), and while an association exists between PKC-mediated cTnI phosphorylation and contractile function (7), the specific role of TnI in the contractile response remains unclear.The activation and expression pattern of multiple PKC isoforms in the heart changes under pathophysiological conditions, which may influence the role of PKC-mediated TnI phosphorylation in the contractile function response. In adult myocardium, the classical ␣ isoform, as well as the novel ␦ and ⑀ isoforms are normally expressed in both rats and humans (8 -10), while expression of the classical ␤ isoform is absent from adult m...

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“…In vitro and animal studies have shown that ET-1 may either elevate or reduce heart rate. [35][36][37] It is thus interesting but nevertheless speculative that direct action of darusentan on cardiac ET A receptors might have contributed to maintaining heart rate at a constant level in our study.…”

Section: Systemic Hemodynamics and Results From Neurohumoral Studiesmentioning

confidence: 77%

St John's wort, depression, and catecholamines

Haller¹

2004

Clinical Pharmacology & Therapeutics

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A mitogen-activated protein kinase is involved in the inotropic but not chronotropic actions of adrenoceptor agonists and endothelin-1

Cited by 8 publications

References 14 publications

Designing Heart Performance by Gene Transfer

Designing Heart Performance by Gene Transfer

Role of Troponin I Phosphorylation in Protein Kinase C-mediated Enhanced Contractile Performance of Rat Myocytes

St John's wort, depression, and catecholamines

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