title: Selective cathepsin S inhibition attenuates atherosclerosis in apolipoprotein E-deficient mice with chronic renal disease.
abstract: Chronic renal disease (CRD) accelerates the development of atherosclerosis. The potent protease cathepsin S cleaves elastin and generates bioactive elastin peptides, thus promoting vascular inflammation and calcification. We hypothesized that selective cathepsin S inhibition attenuates atherogenesis in hypercholesterolemic mice with CRD. CRD was induced by 5/6 nephrectomy in high-fat high-cholesterol fed apolipoprotein E-deficient mice. CRD mice received a diet admixed with 6.6 or 60 mg/kg of the potent and selective cathepsin S inhibitor RO5444101 or a control diet. CRD mice had significantly higher plasma levels of osteopontin, osteocalcin, and osteoprotegerin (204%, 148%, and 55%, respectively; P < 0.05), which were inhibited by RO5444101 (60%, 40%, and 36%, respectively; P < 0.05). Near-infrared fluorescence molecular imaging revealed a significant reduction in cathepsin activity in treated mice. RO5444101 decreased osteogenic activity. Histologic assessment in atherosclerotic plaque demonstrated that RO5444101 reduced immunoreactive cathepsin S (P < 0.05), elastin degradation (P = 0.01), plaque size (P = 0.01), macrophage accumulation (P < 0.01), growth differentiation factor-15 (P = 0.0001), and calcification (alkaline phosphatase activity, P < 0.01; osteocalcin, P < 0.05). Furthermore, cathepsin S inhibitor or siRNA significantly decreased expression of growth differentiation factor-15 and monocyte chemotactic protein-1 in a murine macrophage cell line and human primary macrophages. Systemic inhibition of cathepsin S attenuates the progression of atherosclerotic lesions in 5/6 nephrectomized mice, serving as a potential treatment for atherosclerosis in patients with CRD.
authors: The Center of Excellence in Vascular Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, Brazil.
authors: Jose-Luiz
authors: JL
authors: Figueiredo
authors: The Center of Excellence in Vascular Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, Brazil.
authors: Masanori
authors: M
authors: Aikawa
authors: The Center of Excellence in Vascular Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, Brazil.
authors: Chunyu
authors: C
authors: Zheng
authors: The Center of Excellence in Vascular Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, Brazil.
authors: Jacob
authors: J
authors: Aaron
authors: The Center of Excellence in Vascular Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, Brazil.
authors: Lilian
authors: L
authors: Lax
authors: The Center of Excellence in Vascular Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, Brazil.
authors: Peter
authors: P
authors: Libby
authors: Laboratory of Immunopathology Keizo Asami, Federal University of Pernambuco, Recife, Brazil.
authors: Jose Luiz
authors: JL
authors: de Lima Filho
authors: Pharma Research and Early Development, Hoffman La Roche, Basel, Switzerland.
authors: Sabine
authors: S
authors: Gruener
authors: Pharma Research and Early Development, Hoffman La Roche, Basel, Switzerland.
authors: Jürgen
authors: J
authors: Fingerle
authors: Pharma Research and Early Development, Hoffman La Roche, Basel, Switzerland.
authors: Wolfgang
authors: W
authors: Haap
authors: Pharma Research and Early Development, Hoffman La Roche, Basel, Switzerland.
authors: Guido
authors: G
authors: Hartmann
authors: The Center of Excellence in Vascular Biology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, Brazil. Electronic address: eaikawa@partners.org.
authors: Elena
authors: E
authors: Aikawa
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001158:Arteries / Q000201:enzymology / Q000473:pathology; D050197:Atherosclerosis / Q000150:complications / Q000473:pathology*; D015415:Biomarkers / Q000097:blood; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism; D055436:Growth Differentiation Factor 15 / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007676:Kidney Failure, Chronic / Q000097:blood / Q000201:enzymology* / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010012:Osteogenesis / Q000187:drug effects; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D061205:Vascular Calcification / Q000150:complications / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D018932:Chemokine CCL2; C526140:GDF15 protein, human; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D011480:Protease Inhibitors; D007371:Interferon-gamma; D002403:Cathepsins; C028217:cathepsin S