Matrix Metalloproteinase Inhibition Attenuates Left Ventricular Remodeling and Dysfunction in a Rat Model of Progressive Heart Failure

DOI Web Site 被引用文献8件
  • J. Thomas Peterson
    From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).
  • Hussein Hallak
    From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).
  • Linda Johnson
    From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).
  • Hua Li
    From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).
  • Patrick M. O’Brien
    From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).
  • Drago R. Sliskovic
    From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).
  • Thomas M. A. Bocan
    From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).
  • Mytsi L. Coker
    From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).
  • Takuma Etoh
    From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).
  • Francis G. Spinale
    From the Departments of Cardiovascular Pharmacology (J.T.P., H.L., T.M.A.B.), Pharmacokinetics and Drug Metabolism (H.H.), Biochemistry (L.J.), and Chemistry (P.M.O., D.R.S.), Pfizer Global Research and Development, Ann Arbor, Mich; and Cardiothoracic Surgery, Medical University of South Carolina, Charleston (M.L.C., T.E., F.G.S.).

書誌事項

公開日
2001-05-08
DOI
  • 10.1161/01.cir.103.18.2303
公開者
Ovid Technologies (Wolters Kluwer Health)

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説明

<jats:p><jats:italic>Background</jats:italic>—Matrix metalloproteinase (MMP) activation contributes to tissue remodeling in several disease states, and increased MMP activity has been observed in left ventricular (LV) failure. The present study tested the hypothesis that MMP inhibition would influence LV remodeling and function in developing LV failure.</jats:p><jats:p><jats:italic>Methods and Results</jats:italic>—LV size and function were measured in 5 groups of rats: (1) obese male spontaneously hypertensive heart failure rats (SHHF) at 9 months (n=10), (2) SHHF at 13 months (n=12), (3) SHHF rats treated with an MMP inhibitor during months 9 to 13 (PD166793 5 mg · kg<jats:sup>−1</jats:sup>· d<jats:sup>−1</jats:sup>PO; n=14), (4) normotensive Wistar-Furth rats (WF) at 9 months (n=12), and (5) WF at 13 months (n=12). Plasma concentrations of the MMP inhibitor (116±11 μmol/L) reduced in vitro LV myocardial MMP-2 activity by ≈100%. LV function and geometry were similar in WF rats at 9 and 13 months. LV peak +dP/dt was unchanged at 9 months in SHHF but by 13 months was reduced in the SHHF group compared with WF (3578±477 versus 5983±109 mm Hg/s,<jats:italic>P</jats:italic>≤0.05). LV volume measured at an equivalent ex vivo pressure (10 mm Hg) was increased in SHHF at 9 months compared with WF (443±12 versus 563±33 mL,<jats:italic>P</jats:italic>≤0.05) and increased further by 13 months (899±64 mL,<jats:italic>P</jats:italic>≤0.05). LV myocardial MMP-2 activity was increased by ≈2-fold in SHHF at 9 and 13 months. With MMP inhibition, LV peak +dP/dt was similar to WF values and LV volume was reduced compared with untreated SHHF values (678±28 mL,<jats:italic>P</jats:italic>≤0.05).</jats:p><jats:p><jats:italic>Conclusions</jats:italic>—MMP activity contributes to LV dilation and progression to LV dysfunction in a rodent HF model, and direct MMP inhibition can attenuate this process.</jats:p>

収録刊行物

  • Circulation

    Circulation 103 (18), 2303-2309, 2001-05-08

    Ovid Technologies (Wolters Kluwer Health)

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