title: Bone marrow from blotchy mice is dispensable to regulate blood copper and aortic pathologies but required for inflammatory mediator production in LDLR-deficient mice during chronic angiotensin II infusion.
abstract: BACKGROUND
  The blotchy mouse caused by mutations of ATP7A develops low blood copper and aortic aneurysm and rupture. Although the aortic pathologies are believed primarily due to congenital copper deficiencies in connective tissue, perinatal copper supplementation does not produce significant therapeutic effects, hinting additional mechanisms in the symptom development, such as an independent effect of the ATP7A mutations during adulthood.
  
  
  METHODS
  We investigated if bone marrow from blotchy mice contributes to these symptoms. For these experiments, bone marrow from blotchy mice (blotchy marrow group) and healthy littermate controls (control marrow group) was used to reconstitute recipient mice (irradiated male low-density lipoprotein receptor -/- mice), which were then infused with angiotensin II (1,000 ng/kg/min) for 4 weeks.
  
  
  RESULTS
  By using Mann-Whitney U test, our results showed that there was no significant difference in the copper concentrations in plasma and hematopoietic cells between these 2 groups. And plasma level of triglycerides was significantly reduced in blotchy marrow group compared with that in control marrow group (P < 0.05), whereas there were no significant differences in cholesterol and phospholipids between these 2 groups. Furthermore, a bead-based multiplex immunoassay showed that macrophage inflammatory protein (MIP)-1β, monocyte chemotactic protein (MCP)-1, MCP-3, MCP-5, tissue inhibitor of metalloproteinases (TIMP)-1, and vascular endothelial growth factor (VEGF)-A production was significantly reduced in the plasma of blotchy marrow group compared with that in control marrow group (P < 0.05). More important, although angiotensin II infusion increased maximal external aortic diameters in thoracic and abdominal segments, there was no significant difference in the aortic diameters between these 2 groups. Furthermore, aortic ruptures, including transmural breaks of the elastic laminae in the abdominal segment and lethal rupture in the thoracic segment, were observed in blotchy marrow group but not in control marrow group; however, there was no significant difference in the incidence of aortic ruptures between these 2 groups (P = 0.10; Fisher's exact test).
  
  
  CONCLUSIONS
  Overall, our study indicated that the effect of bone marrow from blotchy mice during adulthood is dispensable in the regulation of blood copper, plasma cholesterol and phospholipids levels, and aortic pathologies, but contributes to a reduction of MIP-1β, MCP-1, MCP-3, MCP-5, TIMP-1, and VEGF-A production and triglycerides concentration in plasma. Our study also hints that bone marrow transplantation cannot serve as an independent treatment option.
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Devon
authors.initials: D
authors.lastname: Harris
authors.affiliation: Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Cang
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Senlin
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX.
authors.forename: Om
authors.initials: O
authors.lastname: Patel
authors.affiliation: Division of Vascular Surgery, Department of Surgery, University of Texas Health Science Center at San Antonio, San Antonio, TX. Electronic address: qinz@uthscsa.edu.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Qin
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics; D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001014:Aortic Aneurysm / Q000097:blood / Q000378:metabolism / Q000503:physiopathology*; D001019:Aortic Rupture / Q000097:blood / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001853:Bone Marrow / Q000378:metabolism* / Q000503:physiopathology; D016026:Bone Marrow Transplantation; D002317:Cardiovascular Agents / Q000008:administration & dosage; D027682:Cation Transport Proteins / Q000235:genetics; D003300:Copper / Q000097:blood / Q000378:metabolism*; D000073840:Copper-Transporting ATPases; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004798:Enzymes / Q000097:blood; D005260:Female; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011973:Receptors, LDL / Q000235:genetics
chemical_list: C486201:Atp7a protein, mouse; D015415:Biomarkers; D002317:Cardiovascular Agents; D027682:Cation Transport Proteins; D016207:Cytokines; D004798:Enzymes; D008055:Lipids; D011973:Receptors, LDL; D000804:Angiotensin II; D003300:Copper; D000251:Adenosine Triphosphatases; D000073840:Copper-Transporting ATPases