title: Differential hypertensive protease expression in the thoracic versus abdominal aorta.
abstract: Hypertension (HTN), which is a major risk factor for cardiovascular morbidity and mortality, can drive pathologic remodeling of the macro- and microcirculation. Patterns of aortic pathology differ, however, suggesting regional heterogeneity of the pressure-sensitive protease systems triggering extracellular matrix remodeling in the thoracic (TA) and abdominal aortas (AA). This study tested the hypothesis that the expression of two major protease systems (matrix metalloproteinases [MMPs] and cathepsins) in the TA and AA would be differentially affected with HTN.
  
  
  
  Normotensive (BPN3) mice at 14-16 weeks of age underwent implantation of osmotic infusion pumps for 28-day angiotensin II (AngII) delivery (1.46 mg/kg/day; BPN3+AngII; n = 8) to induce HTN. The TA and AA were harvested to determine levels of MMP-2, MMP-9, and membrane type 1-MMP, and cathepsins S, K, and L were evaluated in age-matched BPN3 (n = 8) control and BPH2 spontaneously hypertensive mice (non-AngII pathway; n = 7). Blood pressure was monitored via CODA tail cuff plethysmography (Kent Scientific Corporation, Torrington, Conn). Quantitative real-time polymerase chain reaction and immunoblotting/zymography were used to measure MMP and cathepsin messenger RNA expression and protein abundance, respectively. Target protease values were compared within each aortic region via analysis of variance.
  
  
  
  Following 28 days infusion, the BPN3+AngII mice had a 17% increase in systolic blood pressure, matching that of the BPH2 spontaneously hypertensive mice (both P < .05 vs BPN3). MMP-2 gene expression demonstrated an AngII-dependent increase in the TA (P < .05), but MMP-9 was not altered with HTN. Expression of tissue inhibitor of metalloproteinases-1 was markedly increased in TA of BPN3+AngII mice, but tissue inhibitor of metalloproteinases-2 demonstrated decreased expression in the AA of both hypertensive groups (P < .05). Only cathepsin K responded to AngII-induced HTN with significant elevation in the TA of those mice, but expression of cathepsin L and cystatin C was inhibited in AA of both hypertensive groups (P < .05). Apoptotic markers were not significantly elevated in any experimental group.
  
  
  
  By using two different models of HTN, this study has identified pressure-dependent as well as AngII-dependent regional alterations in aortic gene expression of MMPs and cathepsins that may lead to differential remodeling responses in each of the aortic regions. Further studies will delineate mechanisms and may provide targeted therapies to attenuate down-stream aortic pathology based on demonstrated regional heterogeneity.
authors.affiliation: Division of Vascular Surgery, Medical University of South Carolina, Charleston, SC; Division of Cardiothoracic Research, Medical University of South Carolina, Charleston, SC. Electronic address: ruddy@musc.edu.
authors.forename: Jean Marie
authors.initials: JM
authors.lastname: Ruddy
authors.affiliation: Division of Cardiothoracic Research, Medical University of South Carolina, Charleston, SC.
authors.forename: Adam W
authors.initials: AW
authors.lastname: Akerman
authors.affiliation: Division of Cardiothoracic Research, Medical University of South Carolina, Charleston, SC.
authors.forename: Denise
authors.initials: D
authors.lastname: Kimbrough
authors.affiliation: Division of Cardiothoracic Research, Medical University of South Carolina, Charleston, SC.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Nadeau
authors.affiliation: Division of Cardiothoracic Research, Medical University of South Carolina, Charleston, SC.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stroud
authors.affiliation: Division of Cardiothoracic Research, Medical University of South Carolina, Charleston, SC.
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.affiliation: Division of Cardiothoracic Research, Medical University of South Carolina, Charleston, SC; Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC.
authors.forename: John S
authors.initials: JS
authors.lastname: Ikonomidis
authors.affiliation: Division of Cardiothoracic Research, Medical University of South Carolina, Charleston, SC.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Jones
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001012:Aorta, Abdominal / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001013:Aorta, Thoracic / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism; D002403:Cathepsins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: C507096:Mmp14 protein, mouse; D012333:RNA, Messenger; D000804:Angiotensin II; D002403:Cathepsins; D056668:Cathepsin L; C534278:Ctsl protein, mouse; C028217:cathepsin S; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053511:Matrix Metalloproteinase 14