Leukocyte calpain deficiency reduces Angiotensin II-induced inflammation and atherosclerosis but not abdominal aortic aneurysms in mice

Deborah A. Howatt, Anju Balakrishnan, Jessica J. Moorleghen, Latha Muniappan, Debra L. Rateri, Haruhito A. Uchida, Jiro Takano, Takaomi C. Saido, Athar H. Chishti, Laurent Baud, Venkateswaran Subramanian

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19 Citations (Scopus)

Abstract

Objective - Angiotensin II (AngII) infusion profoundly increases activity of calpains, calcium-dependent neutral cysteine proteases, in mice. Pharmacological inhibition of calpains attenuates AngII-induced aortic medial macrophage accumulation, atherosclerosis, and abdominal aortic aneurysm in mice. However, the precise functional contribution of leukocyte-derived calpains in AngII-induced vascular pathologies has not been determined. The purpose of this study was to determine whether calpains expressed in bone marrow (BM)-derived cells contribute to AngII-induced atherosclerosis and aortic aneurysms in hypercholesterolemic mice. Approach and Results - To study whether leukocyte calpains contributed to AngII-induced aortic pathologies, irradiated male low-density lipoprotein receptor-/- mice were repopulated with BM-derived cells that were either wild-type or overexpressed calpastatin, the endogenous inhibitor of calpains. Mice were fed a fat-enriched diet and infused with AngII (1000 ng/kg per minute) for 4 weeks. Overexpression of calpastatin in BM-derived cells significantly attenuated AngII-induced atherosclerotic lesion formation in aortic arches, but had no effect on aneurysm formation. Using either BM-derived cells from calpain-1-deficient mice or mice with leukocyte-specific calpain-2 deficiency generated using cre-loxP recombination technology, further studies demonstrated that independent deficiency of either calpain-1 or -2 in leukocytes modestly attenuated AngII-induced atherosclerosis. Calpastatin overexpression significantly attenuated AngII-induced inflammatory responses in macrophages and spleen. Furthermore, calpain inhibition suppressed migration and adhesion of macrophages to endothelial cells in vitro. Calpain inhibition also significantly decreased hypercholesterolemia-induced atherosclerosis in the absence of AngII. Conclusions - The present study demonstrates a pivotal role for BM-derived calpains in mediating AngII-induced atherosclerosis by influencing macrophage function.

Original languageEnglish
Pages (from-to)835-845
Number of pages11
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume36
Issue number5
DOIs
Publication statusPublished - May 1 2016

Keywords

  • angiotensin II
  • atherosclerosis
  • calpain
  • inflammation
  • macrophages

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Howatt, D. A., Balakrishnan, A., Moorleghen, J. J., Muniappan, L., Rateri, D. L., Uchida, H. A., Takano, J., Saido, T. C., Chishti, A. H., Baud, L., & Subramanian, V. (2016). Leukocyte calpain deficiency reduces Angiotensin II-induced inflammation and atherosclerosis but not abdominal aortic aneurysms in mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 36(5), 835-845. https://doi.org/10.1161/ATVBAHA.116.307285