The Multifunctional Ca2+/Calmodulin-Dependent Kinase IIδ (CaMKIIδ) Regulates Arteriogenesis in a Mouse Model of Flow-Mediated Remodeling

Jason A Scott; Paula J Klutho; Ramzi El Accaoui; Emily Nguyen; Ashlee N Venema; Litao Xie; Shuxia Jiang; Megan Dibbern; Sabrina Scroggins; Anand M Prasad; Elisabeth D Luczak; Melissa K Davis; Weiwei Li; Xiaoqun Guan; Johannes Backs; Annette J Schlueter; Robert M Weiss; Francis J Miller; Mark E Anderson; Isabella M Grumbach

doi:10.1371/journal.pone.0071550

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The Multifunctional Ca2+/Calmodulin-Dependent Kinase IIδ (CaMKIIδ) Regulates Arteriogenesis in a Mouse Model of Flow-Mediated Remodeling

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The Multifunctional Ca2+/Calmodulin-Dependent Kinase IIδ (CaMKIIδ) Regulates Arteriogenesis in a Mouse Model of Flow-Mediated Remodeling

Jason A Scott, Paula J Klutho, Ramzi El Accaoui, Emily Nguyen, Ashlee N Venema, Litao Xie, Shuxia Jiang, Megan Dibbern, Sabrina Scroggins, Anand M Prasad, …

PloS one, Vol.8(8), pp.e71550-e71550

2013

DOI: 10.1371/journal.pone.0071550

PMCID: PMC3738514

PMID: 23951185

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Abstract

Objective Sustained hemodynamic stress mediated by high blood flow promotes arteriogenesis, the outward remodeling of existing arteries. Here, we examined whether Ca2+/calmodulin-dependent kinase II (CaMKII) regulates arteriogenesis. Methods and Results Ligation of the left common carotid led to an increase in vessel diameter and perimeter of internal and external elastic lamina in the contralateral, right common carotid. Deletion of CaMKIIδ (CaMKIIδ−/−) abolished this outward remodeling. Carotid ligation increased CaMKII expression and was associated with oxidative activation of CaMKII in the adventitia and endothelium. Remodeling was abrogated in a knock-in model in which oxidative activation of CaMKII is abolished. Early after ligation, matrix metalloproteinase 9 (MMP9) was robustly expressed in the adventitia of right carotid arteries of WT but not CaMKIIδ−/− mice. MMP9 mainly colocalized with adventitial macrophages. In contrast, we did not observe an effect of CaMKIIδ deficiency on other proposed mediators of arteriogenesis such as expression of adhesion molecules or smooth muscle proliferation. Transplantation of WT bone marrow into CaMKIIδ−/− mice normalized flow-mediated remodeling. Conclusion CaMKIIδ is activated by oxidation under high blood flow conditions and is required for flow-mediated remodeling through a mechanism that includes increased MMP9 expression in bone marrow-derived cells invading the arterial wall.

Bone Marrow Transplantation

Ultrasonography

Carotid Artery, Common - diagnostic imaging

Up-Regulation

Carotid Artery, Common - ultrastructure

Oxidation-Reduction

Mice, Inbred C57BL

Cells, Cultured

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics

Carotid Artery, Common - physiology

Matrix Metalloproteinase 9 - metabolism

Animals

Carotid Artery Injuries - enzymology

Matrix Metalloproteinase 9 - genetics

Gene Deletion

Mice

Carotid Artery Injuries - diagnostic imaging

Enzyme Activation

Neovascularization, Physiologic

Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism

Details

Title: Subtitle: The Multifunctional Ca2+/Calmodulin-Dependent Kinase IIδ (CaMKIIδ) Regulates Arteriogenesis in a Mouse Model of Flow-Mediated Remodeling
Creators: Jason A Scott - Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Paula J Klutho
Ramzi El Accaoui
Emily Nguyen
Ashlee N Venema
Litao Xie
Shuxia Jiang
Megan Dibbern
Sabrina Scroggins
Anand M Prasad
Elisabeth D Luczak
Melissa K Davis
Weiwei Li
Xiaoqun Guan
Johannes Backs
Annette J Schlueter
Robert M Weiss
Francis J Miller
Mark E Anderson
Isabella M Grumbach
Resource Type: Journal article
Publication Details: PloS one, Vol.8(8), pp.e71550-e71550
DOI: 10.1371/journal.pone.0071550
PMID: 23951185
PMCID: PMC3738514
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: R01 HL 079031 / NHLBI NIH HHS R01 HL 070250 / NHLBI NIH HHS R01 HL 108932 / NHLBI NIH HHS R01 AA019568 / NIAAA NIH HHS T32 HL007121 / NHLBI NIH HHS R01 HL108932 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS R01 HL079031 / NHLBI NIH HHS R01 HL070250 / NHLBI NIH HHS I01 BX000163 / BLRD VA R01 HL096652 / NHLBI NIH HHS R01 AA 019568 / NIAAA NIH HHS
Language: English
Date published: 2013
Academic Unit: Radiology; Pathology; Cardiovascular Medicine; Radiation Oncology; Obstetrics and Gynecology; Internal Medicine
Record Identifier: 9984046935402771

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