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 (AIIϩP; n ϭ 8). A second group (n ϭ 9) underwent the same AIIϩP 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 AIIϩP 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, AIIϩP activated MMP9 and MMP2 and specifically exacerbated diastolic stiffening (ϩ130% in chamber stiffness). PD166793 cotreatment prevented these changes, although myocardial collagen content, subtype, and cross-linking were unaltered. AIIϩP also reduced ATP, free energy of ATP hydrolysis (⌬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.

Excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies afterload-induced diastolic dysfunction in the type 2 diabetic heart

“…Recently, Cheng et al [29] reported that AMPD3-deficient mice exhibited increased ATP levels in erythrocytes, in which AMPD3 is a dominant isoform. The findings in the two studies [28,29] and the present findings support the notion that up-regulated AMPD activity is responsible for ATP depletion and that restoration of AMPD activity could be a therapeutic target for diastolic dysfunction in diabetic hearts.…”

“…Although metformin has been reported to inhibit AMPDs in the skeletal muscle (AMPD1) [26] and liver (AMPD2) [27], treatment of the myocardium with 50 μM-10 mM metformin or its addition to the assay solution in vitro did not reduce the activity of cardiac AMPD (AMPD3) in our experiments (data not shown). Interestingly, Paolocci et al [28] showed that treatment with a metalloproteinase inhibitor (PD166793) partly inhibited AMPD activity, restored total adenine nucleotides and improved diastolic function in a canine model of heart failure. Recently, Cheng et al [29] reported that AMPD3-deficient mice exhibited increased ATP levels in erythrocytes, in which AMPD3 is a dominant isoform.…”

Mitochondrial Integrity and Function in the Progression of Early Pressure Overload–Induced Left Ventricular Remodeling

“…Similarly, fetal gene expression and interstitial fibrosis in the LV myocardium were increased in all phenotypes and most strikingly in the MOD phenotype. Moreover, MMP‐2 and MMP‐9 expression was increased, but more importantly, TIMP‐1 expression was robustly decreased in the MOD phenotype, suggesting robust increases in MMP‐2 and MMP‐9 activities and extracellular matrix remodeling in this phenotype and as previously shown 20, 21, 22. These data further highlight the important role of TIMP‐1 as a nodal modulator of MMPs activity, extracellular matrix and myocardial remodeling, at least in this model of HF and similar to what has been shown in human HF 19…”

High serum levels of procollagen type III N-terminal amino peptide in patients with congenital heart disease

“…In the same context, the relationships between various serological markers of fibrogenesis and ventricular diastolic dysfunction (stiffening) are of great clinical interest because myocardial fibrosis is an important pathophysiological process underlying ventricular stiffening 37 38. Indeed, several studies have described a close correlation between serum levels of PIIIP and diastolic dysfunction in adults 34 39.…”