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

Author

Paolocci N, Tavazzi B, Biondi R, Gluzband YA, Amorini AM, Tocchetti CG, Hejazi M, Caturegli PM, Kajstura J, Lazzarino G, and Kass DA

Subjects
AMP Deaminase antagonists & inhibitors, Animals, Collagen metabolism, Disease Models, Animal, Dogs, Dose-Response Relationship, Drug, Energy Metabolism, Enzyme Inhibitors pharmacology, Hydroxamic Acids pharmacology, Male, Oligopeptides pharmacology, Ventricular Dysfunction enzymology, Ventricular Dysfunction metabolism, AMP Deaminase metabolism, Cardiac Output, Low complications, Cardiac Output, Low enzymology, Cardiac Output, Low metabolism, Metalloproteases antagonists & inhibitors, Phosphates metabolism, Ventricular Dysfunction etiology
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.

Published
2006
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2. Metalloproteinase Inhibitor Counters High-Energy Phosphate Depletion and AMP Deaminase Activity Enhancing Ventricular Diastolic Compliance in Subacute Heart Failure

Author

Nazareno Paolocci, Patrizio M. Caturegli, Carlo G. Tocchetti, Mehrdad Hejazi, Roberto Biondi, Giuseppe Lazzarino, Jan Kajstura, David A. Kass, Yehezkiel A. Gluzband, Angela Maria Amorini, Barbara Tavazzi, Paolocci, N, Tavazzi, B, Biondi, R, Gluzband, Ya, Amorini, Am, Tocchetti, CARLO GABRIELE, Hejazi, M, Caturegli, Pm, Kajstura, J, Lazzarino, G, and Kass, Da

Subjects
Male, High-energy phosphate, medicine.medical_specialty, AMP deaminase activity, Cardiac Output, Low, Diastole, Matrix metalloproteinase, Hydroxamic Acids, AMP Deaminase, Phosphates, Phosphocreatine, chemistry.chemical_compound, Dogs, Internal medicine, Ventricular Dysfunction, medicine, Animals, OXIDATIVE STRESS, Enzyme Inhibitors, Pharmacology, Dose-Response Relationship, Drug, Chemistry, RAT HEARTS, AMP deaminase, AMP DEAMINASE, DILATED CARDIOMYOPATHY, REGULATORY PROPERTIES, ANGIOTENSIN-II, ENERGY METABOLISM, medicine.disease, Angiotensin II, Disease Models, Animal, Endocrinology, Heart failure, Metalloproteases, cardiovascular system, Molecular Medicine, Collagen, Energy Metabolism, Oligopeptides
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-methylbutyricacid] 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 (Delta G(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.

Published
2006

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