Calmodulin kinase II is required for angiotensin II-mediated vascular smooth muscle hypertrophy

Hui Li; Weiwei Li; Arun K Gupta; Peter J Mohler; Mark E Anderson; Isabella M Grumbach

doi:10.1152/ajpheart.01014.2009

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Calmodulin kinase II is required for angiotensin II-mediated vascular smooth muscle hypertrophy

Journal article

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Peer reviewed

Calmodulin kinase II is required for angiotensin II-mediated vascular smooth muscle hypertrophy

Hui Li, Weiwei Li, Arun K Gupta, Peter J Mohler, Mark E Anderson and Isabella M Grumbach

American journal of physiology. Heart and circulatory physiology, Vol.298(2), pp.H688-H698

02/2010

DOI: 10.1152/ajpheart.01014.2009

PMCID: PMC2822565

PMID: 20023119

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Abstract

Despite our understanding that medial smooth muscle hypertrophy is a central feature of vascular remodeling, the molecular pathways underlying this pathology are still not well understood. Work over the past decade has illustrated a potential role for the multifunctional calmodulin-dependent kinase CaMKII in smooth muscle cell contraction, growth, and migration. Here we demonstrate that CaMKII is enriched in vascular smooth muscle (VSM) and that CaMKII inhibition blocks ANG II-dependent VSM cell hypertrophy in vitro and in vivo. Specifically, systemic CaMKII inhibition with KN-93 prevented ANG II-mediated hypertension and medial hypertrophy in vivo. Adenoviral transduction with the CaMKII peptide inhibitor CaMKIIN abrogated ANG II-induced VSM hypertrophy in vitro, which was augmented by overexpression of CaMKII-δ2. Finally, we identify the downstream signaling components critical for ANG II- and CaMKII-mediated VSM hypertrophy. Specifically, we demonstrate that CaMKII induces VSM hypertrophy by regulating histone deacetylase 4 (HDAC4) activity, thereby stimulating activity of the hypertrophic transcription factor MEF2. MEF2 transcription is activated by ANG II in vivo and abrogated by the CaMKII inhibitor KN-93. Together, our studies identify a complete pathway for ANG II-triggered arterial VSM hypertrophy and identify new potential therapeutic targets for chronic human hypertension.

MEF2

histone deacetylase

remodeling

Details

Title: Subtitle: Calmodulin kinase II is required for angiotensin II-mediated vascular smooth muscle hypertrophy
Creators: Hui Li - Department of Internal Medicine and
Weiwei Li - Department of Internal Medicine and
Arun K Gupta - Department of Internal Medicine and
Peter J Mohler - Department of Internal Medicine and
Mark E Anderson - Department of Internal Medicine and
Isabella M Grumbach - Department of Internal Medicine and
Resource Type: Journal article
Publication Details: American journal of physiology. Heart and circulatory physiology, Vol.298(2), pp.H688-H698
DOI: 10.1152/ajpheart.01014.2009
PMID: 20023119
PMCID: PMC2822565
NLM abbreviation: Am J Physiol Heart Circ Physiol
ISSN: 0363-6135
eISSN: 1522-1539
Publisher: American Physiological Society
Language: English
Date published: 02/2010
Academic Unit: Pathology; Cardiovascular Medicine; Radiation Oncology; Internal Medicine
Record Identifier: 9984094352402771

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