The control of Ca2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension.

Imagen de Manuel F Navedo
TítuloThe control of Ca2+ influx and NFATc3 signaling in arterial smooth muscle during hypertension.
Publication TypeJournal Article
Year of Publication2008
AutoresNieves-Cintrón, M, Amberg, GC, Navedo, MF, Molkentin, JD, Santana, LF
JournalProc Natl Acad Sci U S A
Volume105
Issue40
Pagination15623-8
Date Published2008 Oct 7
ISSN1091-6490
Palabras claveAngiotensin II, Animals, Arteries, Calcium, Calcium Channels, L-Type, Humans, Hypertension, Mice, Mice, Knockout, Muscle, Smooth, Vascular, NFATC Transcription Factors, Protein Kinase C-alpha, Rats, Rats, Sprague-Dawley, Signal Transduction
Abstract

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.

DOI10.1073/pnas.0808759105
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID18832165
PubMed Central IDPMC2557027