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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume298
Issue number2
DOIs
StatePublished - 2010
Externally publishedYes

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Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases
Vascular Smooth Muscle
Angiotensin II
Hypertrophy
Smooth Muscle Myocytes
MEF2 Transcription Factors
Hypertension
Histone Deacetylases
Muscle Contraction
Smooth Muscle
Pathology
Peptides

Keywords

  • Histone deacetylase
  • MEF2
  • Remodeling

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Calmodulin kinase II is required for angiotensin II-mediated vascular smooth muscle hypertrophy. / Li, Hui; Li, Weiwei; Gupta, Arun K.; Mohler, Peter J.; Anderson, Mark; Grumbach, Isabella M.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 298, No. 2, 2010.

Research output: Contribution to journalArticle

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