Document Detail

The control of Ca2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension.
MedLine Citation:
PMID:  18832165     Owner:  NLM     Status:  MEDLINE    
Many excitable cells express L-type Ca(2+) channels (LTCCs), which participate in physiological and pathophysiological processes ranging from memory, secretion, and contraction to epilepsy, heart failure, and hypertension. Clusters of LTCCs can operate in a PKCalpha-dependent, high open probability mode that generates sites of sustained Ca(2+) influx called "persistent Ca(2+) sparklets." Although increased LTCC activity is necessary for the development of vascular dysfunction during hypertension, the mechanisms leading to increased LTCC function are unclear. Here, we tested the hypothesis that increased PKCalpha and persistent Ca(2+) sparklet activity contributes to arterial dysfunction during hypertension. We found that PKCalpha and persistent Ca(2+) sparklet activity is indeed increased in arterial myocytes during hypertension. Furthermore, in human arterial myocytes, PKCalpha-dependent persistent Ca(2+) sparklets activated the prohypertensive calcineurin/NFATc3 signaling cascade. These events culminated in three hallmark signs of hypertension-associated vascular dysfunction: increased Ca(2+) entry, elevated arterial [Ca(2+)](i), and enhanced myogenic tone. Consistent with these observations, we show that PKCalpha ablation is protective against the development of angiotensin II-induced hypertension. These data support a model in which persistent Ca(2+) sparklets, PKCalpha, and calcineurin form a subcellular signaling triad controlling NFATc3-dependent gene expression, arterial function, and blood pressure. Because of the ubiquity of these proteins, this model may represent a general signaling pathway controlling gene expression and cellular function.
Madeline Nieves-Cintrón; Gregory C Amberg; Manuel F Navedo; Jeffery D Molkentin; Luis F Santana
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2008-10-01
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  105     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2008 Oct 
Date Detail:
Created Date:  2008-10-08     Completed Date:  2008-11-28     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  15623-8     Citation Subset:  IM    
Department of Physiology and Biophysics, University of Washington, Box 357290, Seattle, WA 98195, USA.
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MeSH Terms
Angiotensin II / administration & dosage
Arteries / metabolism
Calcium / metabolism*
Calcium Channels, L-Type / metabolism
Hypertension / metabolism*
Mice, Knockout
Muscle, Smooth, Vascular / metabolism*
NFATC Transcription Factors / genetics,  metabolism*
Protein Kinase C-alpha / metabolism
Rats, Sprague-Dawley
Signal Transduction*
Reg. No./Substance:
0/Calcium Channels, L-Type; 0/NFATC Transcription Factors; 0/transcription factor NF-AT c3; 11128-99-7/Angiotensin II; 7440-70-2/Calcium; EC Kinase C-alpha

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