title: Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats.
abstract: OBJECTIVE
  We sought to elucidate how the local activation of matrix metalloproteinases (MMPs) is balanced by that of the endogenous tissue inhibitors of MMP (TIMPs) during left ventricular (LV) remodeling.
  
  
  BACKGROUND
  Although it is known that the extracellular matrix (ECM) must be altered during LV remodeling, its local regulation has not been fully elucidated.
  
  
  METHODS
  In Dahl salt-sensitive rats with hypertension, in which a stage of concentric, compensated left ventricular hypertrophy (LVH) at 11 weeks is followed by a distinct stage of congestive heart failure (CHF) with LV enlargement and dysfunction at 17 weeks, we determined protein and messenger ribonucleic acid (mRNA) levels of LV myocardial TIMP-2 and -4 and MMP-2, as well as their concomitant activities.
  
  
  RESULTS
  No changes were found at the LVH stage. However, during the transition to CHF, TIMP-2 and -4 activities, protein and mRNA levels were all sharply increased. At the same time, the MMP-2 mRNA and protein levels and activities, as determined by gelatin zymography, as well as by an antibody capture assay, showed a substantial increase during the transition to CHF. The net MMP activities were closely related to increases in LV diameter (r = 0.763) and to systolic wall stress (r = 0.858) in vivo.
  
  
  CONCLUSIONS
  Both TIMPs and MMP-2 remained inactive during hypertrophy, per se; they were activated during the transition to CHF. At this time, the activation of MMP-2 surpassed that of TIMPs, possibly resulting in ECM breakdown and progression of LV enlargement.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Iwanaga
authors.forename: Takeshi
authors.initials: T
authors.lastname: Aoyama
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Kihara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Onozawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoneda
authors.forename: Shigetake
authors.initials: S
authors.lastname: Sasayama
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology*; D017379:Hypertrophy, Left Ventricular / Q000150:complications* / Q000201:enzymology*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008955:Models, Cardiovascular; D009929:Organ Size / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases