Metalloproteinase inhibitor counters high-energy phosphate depletion and AMP deaminase activity enhancing ventricular diastolic compliance in subacute heart failure

Nazareno Paolocci, Barbara Tavazzi, Roberto Biondi, Yehezkiel A. Gluzband, Angela Maria Amorini, Carlo G. Tocchetti, Mehrdad Hejazi, Patrizio M. Caturegli, Jan Kajstura, Giuseppe Lazzarino, David A. Kass

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiac matrix metalloproteinases (MMPs) stimulated by the sympathomimetic action of angiotensin II (AII) exacerbate chamber diastolic stiffening in models of subacute heart failure. Here we tested the hypothesis that MMP inhibition prevents such stiffening by favorably modulating high-energy phosphate (HEP) stores more than by effects on matrix remodeling. Dogs were administered AII i.v. for 1 week with tachypacing super-imposed in the last two days (AII+P; n = 8). A second group (n = 9) underwent the same AII+P protocol but was preceded by oral treatment with an MMP inhibitor PD166793 [(S)-2-(4-bromo-biphenyl-4-sulfonylamino-3-methyl butyric acid] 1 week before and during the AII+P period. Pressure-volume analysis was performed in conscious animals, and myocardial tissue was subjected to in vitro and in situ zymography, collagen content, and HEP analysis (high-performance liquid chromatography). As reported previously, AII+P activated MMP9 and MMP2 and specifically exacerbated diastolic stiffening (+130% in chamber stiffness). PD166793 cotreatment prevented these changes, although myocardial collagen content, subtype, and cross-linking were unaltered. AII+P also reduced ATP, free energy of ATP hydrolysis (ΔGATP), and phosphocreatine while increasing free [ADP], AMP catabolites (nucleoside-total purines), and lactate. PD166793 reversed most of these changes, in part due to its inhibition of AMP deaminase. MMP activation may influence cardiac diastolic function by mechanisms beyond modulation of extracellular matrix. Interaction between MMP activation and HEP metabolism may play an important role in mediating diastolic dysfunction. Furthermore, these data highlight a potential major role for increased AMP deaminase activity in diastolic dysfunction.

Original languageEnglish (US)
Pages (from-to)506-513
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume317
Issue number2
DOIs
StatePublished - May 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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