title: Activation of matrix metalloproteinases precedes left ventricular remodeling in hypertensive heart failure rats: its inhibition as a primary effect of Angiotensin-converting enzyme inhibitor.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) are activated in dilated failing hearts, and angiotensin-converting enzyme (ACE) inhibition prevents left ventricular (LV) dilatation. However, it remains unclear whether activation of MMPs precedes or is secondary to LV remodeling, and an effect of ACE inhibition on MMPs is unknown.
  
  
  RESULTS
  Dahl salt-sensitive rats fed a high-salt diet from 8 weeks served as the hypertensive heart failure (HF) model. LV echo, histological study, measurement of mRNA levels, and gelatin zymography were performed before (at 23 weeks) and after (at 26 weeks) the development of LV dilatation and pulmonary edema. The same procedures were conducted in the HF model rats treated with a subdepressor dose of ACE inhibitor (enalapril 5 mg x kg(-1) x d(-1)) from 9 weeks. Rats fed on normal chow served as age-matched controls. In the untreated HF model rats, gene expression of MMP-2 and MMP-9 and tissue gelatinase activity were elevated at 23 weeks without LV dilatation. LV dilatation, LV systolic dysfunction, and pulmonary edema occurred at 26 weeks, with further enhancement of the expression and activity of MMPs. ACE inhibition prevented such geometrical and functional deterioration. The gene expression and activity of MMPs were suppressed by ACE inhibition at 23 weeks without a decrease in blood pressure, and the suppressive effects continued at 26 weeks.
  
  
  CONCLUSIONS
  MMPs are likely to trigger and promote LV remodeling, and ACE inhibition directly exerts inhibitory effect on MMPs, leading to the prevention of LV remodeling and dysfunction.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mano
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Nishikawa
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshida
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miwa
authors.forename: Tohru
authors.initials: T
authors.lastname: Masuyama
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D004452:Echocardiography; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011654:Pulmonary Edema / Q000209:etiology / Q000517:prevention & control; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020303:Rats, Inbred Dahl; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000494:pharmacology; D018487:Ventricular Dysfunction, Left / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D020257:Ventricular Remodeling / Q000187:drug effects / Q000235:genetics*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D011480:Protease Inhibitors; D012333:RNA, Messenger; D019716:Tissue Inhibitor of Metalloproteinase-2; D004656:Enalapril; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9