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

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-delta2. 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.

• Authors: Hui Li, Weiwei Li, Arun K Gupta, Peter J Mohler, Mark E Anderson, Isabella M Grumbach
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 298 Issue 2 Pg. H688-98 (Feb 2010) ISSN: 1522-1539 [Electronic] United States
• PMID: 20023119 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Benzylamines
• Calcium-Binding Proteins
• Camk2n1 protein, rat
• Carrier Proteins
• MADS Domain Proteins
• MEF2 Transcription Factors
• MEF2A protein, rat
• Myogenic Regulatory Factors
• Protein Kinase Inhibitors
• Sulfonamides
• Angiotensin II
• KN 93
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Histone Deacetylases

Topics

• Angiotensin II (metabolism)
• Animals
• Aorta (metabolism, pathology)
• Benzylamines (pharmacology)
• Calcium-Binding Proteins
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (antagonists & inhibitors, drug effects, metabolism)
• Carrier Proteins (metabolism)
• Cells, Cultured
• Disease Models, Animal
• Histone Deacetylases (metabolism)
• Hypertrophy
• MADS Domain Proteins (metabolism)
• MEF2 Transcription Factors
• Male
• Muscle, Smooth, Vascular (metabolism, pathology)
• Myogenic Regulatory Factors (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (physiology)
• Sulfonamides (pharmacology)