Calmodulin kinase II is required for angiotensin II-mediated vascular smooth muscle hypertrophy.
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.
Li
Hui
H
Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
Li
Weiwei
W
Gupta
Arun K
AK
Mohler
Peter J
PJ
Anderson
Mark E
ME
Grumbach
Isabella M
IM
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001596:Benzylamines / Q000494:pharmacology; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006655:Histone Deacetylases / Q000378:metabolism; D006984:Hypertrophy; D026161:MADS Domain Proteins / Q000378:metabolism; D064326:MEF2 Transcription Factors; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000804:Angiotensin II; D001596:Benzylamines; D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002352:Carrier Proteins; D006655:Histone Deacetylases; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C581829:Camk2n1 protein, rat; C578037:MEF2A protein, rat; C072105:KN 93; D000096926:Benzenesulfonamides