Role of myosin light chain kinase in cardiotrophin-1-induced cardiac myofibroblast cell migration

Freed, Darren H., Chilton, Lisa, Li, Yun, Dangerfield, Aran L., Raizman, Joshua E., Rattan, Sunil G., Visen, Neeraj, Hryshko, Larry V., and Dixon, Ian M.C. (2011) Role of myosin light chain kinase in cardiotrophin-1-induced cardiac myofibroblast cell migration. American Journal of Physiology-Heart and Circulatory Physiology, 301. H514-H522.

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Abstract

Chemotactic movement of myofibroblasts is recognized as a common means for their sequestration to the site of tissue injury. Following myocardial infarction (MI), recruitment of cardiac myofibroblasts to the infarct scar is a critical step in wound healing. Contractile myofibroblasts express embryonic smooth muscle myosin, α-smooth muscle actin, as well as collagens I and III. We examined the effects of cardiotrophin-1 (CT-1) in the induction of primary rat ventricular myofibroblast motility. Changes in membrane potential (Em) and Ca2+ entry were studied to reveal the mechanisms for induction of myofibroblast migration. CT-1-induced cardiac myofibroblast cell migration, which was attenuated through the inhibition of JAK2 (25 μM AG490), and myosin light chain kinase (20 μM ML-7). Inhibition of K+ channels (1 mM tetraethylammonium or 100 μM 4-aminopyridine) and nonselective cation channels by 10 μM gadolinium (Gd3+) significantly reduced migration in the presence of CT-1. CT-1 treatment caused a significant increase in myosin light chain phosphorylation, which could be inhibited by incubation in Ca2+-free conditions or by application of AG490, ML-7, and W7 (100 μM; calmodulin inhibitor). Monitoring myofibroblast membrane potential with potentiometric fluorescent DiBAC4(3) dye revealed a biphasic response to CT-1 consisting of an initial depolarization followed by hyperpolarization. Increased intracellular Ca2+, as assessed by fluo 3, occurred immediately after membrane depolarization and attenuated at the time of maximal hyperpolarization. CT-1 exerts chemotactic effects via multiple parallel signaling modalities in ventricular myofibroblasts, including changes in membrane potential, alterations in intracellular calcium, and activation of a number of intracellular signaling pathways. Further study is warranted to determine the precise role of K+ currents in this process.

Item ID: 18626
Item Type: Article (Refereed Research - C1)
Keywords: myocardial infarction; wound healing; membrane potential; cardiac fibroblast; cardiac fibrosis
ISSN: 1522-1539
Funders: Canadian Institutes of Health Research, IMPACT/Canadian Institutes for Health Research program, St. Boniface Hospital and Research Foundation, Heart and Stroke Foundation of Manitoba
Date Deposited: 09 Nov 2011 07:14
FoR Codes: 06 BIOLOGICAL SCIENCES > 0606 Physiology > 060602 Animal Physiology - Cell @ 70%
06 BIOLOGICAL SCIENCES > 0606 Physiology > 060601 Animal Physiology - Biophysics @ 20%
11 MEDICAL AND HEALTH SCIENCES > 1102 Cardiovascular Medicine and Haematology > 110201 Cardiology (incl Cardiovascular Diseases) @ 10%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920103 Cardiovascular System and Diseases @ 100%
Citation Count from Web of Science Web of Science 2
Downloads: Total: 3
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