title: Metalloproteinase inhibitor counters high-energy phosphate depletion and AMP deaminase activity enhancing ventricular diastolic compliance in subacute heart failure.
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 superimposed 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 (DeltaG(ATP)), 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.
authors.affiliation: Division of Cardiology, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205, USA. npaoloc1@jhmi.edu
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
authors.forename: Barbara
authors.initials: B
authors.lastname: Tavazzi
authors.forename: Roberto
authors.initials: R
authors.lastname: Biondi
authors.forename: Yehezkiel A
authors.initials: YA
authors.lastname: Gluzband
authors.forename: Angela Maria
authors.initials: AM
authors.lastname: Amorini
authors.forename: Carlo G
authors.initials: CG
authors.lastname: Tocchetti
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Hejazi
authors.forename: Patrizio M
authors.initials: PM
authors.lastname: Caturegli
authors.forename: Jan
authors.initials: J
authors.lastname: Kajstura
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lazzarino
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
mesh_terms: D000659:AMP Deaminase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D002303:Cardiac Output, Low / Q000150:complications / Q000201:enzymology / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000494:pharmacology; D008297:Male; D045726:Metalloproteases / Q000037:antagonists & inhibitors*; D009842:Oligopeptides / Q000494:pharmacology; D010710:Phosphates / Q000378:metabolism*; D018754:Ventricular Dysfunction / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism
chemical_list: C370242:(R)-2-(4'-bromo-biphenyl-4-sulfonyl-amino)-3-methyl-butyric acid; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D009842:Oligopeptides; D010710:Phosphates; D003094:Collagen; D045726:Metalloproteases; D000659:AMP Deaminase