Deborah A Howatt1, Anju Balakrishnan1, Jessica J Moorleghen1, Latha Muniappan1, Debra L Rateri1, Haruhito A Uchida1, Jiro Takano1, Takaomi C Saido1, Athar H Chishti1, Laurent Baud1, Venkateswaran Subramanian2. 1. From the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.). 2. From the Saha Cardiovascular Research Center (D.A.H., A.B., J.J.M., L.M., D.L.R.), and Department of Physiology (V.S.), University of Kentucky, Lexington; Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan (H.A.U.); Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Saitama, Japan (J.T., T.C.S.); Department of Developmental, Molecular, and Chemical Biology, Tufts University School of Medicine, Boston, MA (A.H.C.); and INSERM, Université Pierre et Marie Curie-Paris, Paris, France (L.B.). venkat.subramanian@uky.edu.
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.
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 hypercholesterolemicmice. 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.
Authors: R Donadelli; M Abbate; C Zanchi; D Corna; S Tomasoni; A Benigni; G Remuzzi; C Zoja Journal: Am J Kidney Dis Date: 2000-12 Impact factor: 8.860
Authors: Edwin Kanters; Manolis Pasparakis; Marion J J Gijbels; Monique N Vergouwe; Iris Partouns-Hendriks; Remond J A Fijneman; Björn E Clausen; Irmgard Förster; Mark M Kockx; Klaus Rajewsky; Georg Kraal; Marten H Hofker; Menno P J de Winther Journal: J Clin Invest Date: 2003-10 Impact factor: 14.808
Authors: Nan Wang; Wengen Chen; Patrick Linsel-Nitschke; Laurent O Martinez; Birgit Agerholm-Larsen; David L Silver; Alan R Tall Journal: J Clin Invest Date: 2003-01 Impact factor: 14.808
Authors: Steven J Forrester; George W Booz; Curt D Sigmund; Thomas M Coffman; Tatsuo Kawai; Victor Rizzo; Rosario Scalia; Satoru Eguchi Journal: Physiol Rev Date: 2018-07-01 Impact factor: 37.312
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Aleksandr E Vendrov; Mark D Stevenson; Samthosh Alahari; Hua Pan; Samuel A Wickline; Nageswara R Madamanchi; Marschall S Runge Journal: J Am Heart Assoc Date: 2017-10-27 Impact factor: 5.501