Showing papers by "Francis G. Spinale published in 2004"

Targeted Overexpression of Noncleavable and Secreted Forms of Tumor Necrosis Factor Provokes Disparate Cardiac Phenotypes

Abstract: Background— Recent studies suggest that posttranslation processing or “shedding” (ie, secretion) of tumor necrosis factor (TNF) by tumor necrosis factor-α converting enzyme (TACE) may contribute to the left ventricular (LV) remodeling that occurs in the failing human heart. Methods and Results— To address the functional significance of TNF shedding, we generated lines of transgenic mice with targeted overexpression of secreted wild-type (MHCsTNF2) TNF and overexpression of a mutated noncleavable transmembrane form of TNF (MHCmTNF). Both lines of mice had overlapping levels of myocardial TNF protein; however, the phenotypes of the MHCsTNF2 and MHCmTNF mice were strikingly disparate. Whereas the MHCmTNF mice developed a concentric LV hypertrophy phenotype, the MHCsTNF2 mice developed a dilated LV phenotype. The fibrillar collagen weave in MHCmTNF mice with concentric hypertrophy was characterized by thick collagen fibrils and increased collagen content, whereas the fibrillar collagen weave in the MHCsTNF2 m...

Effects of Deletion of the Tissue Inhibitor of Matrix Metalloproteinases-1 Gene on the Progression of Murine Thoracic Aortic Aneurysms

Abstract: Objective— The cause of thoracic aortic aneurysms (TAAs) is poorly understood. Previous work has suggested an association between development of aortic aneurysms and matrix metalloproteinase (MMP) activity. We hypothesized that removal of the primary endogenous aortic MMP inhibitor (TIMP) through TIMP-1 gene deletion will increase TAA progression. Methods and Results— The descending thoracic aortas of wild-type 129 SvE and TIMP-1 gene knockout (TIMP-1 −/− ) mice were exposed to 0.5 mol/L CaCl 2 for 15 minutes, with terminal studies performed at 4 or 8 weeks. TAA lumen diameter was measured using confocal microscopy and normalized to the ascending aorta. In addition, sections were studied with in situ zymography and immunohistochemistry staining for MMP-9. Both wild-type [TAA/ascending ratio (mean±SEM): control, 0.85±0.02 (n=14); 4 weeks, 1.00±0.03 (n=13); 8 weeks, 1.05±0.10 (n=9)] and TIMP-1 −/− [control, 0.98±0.04 (n=11); 4 weeks, 1.10±0.03 (n =21); 8 weeks, 1.22±0.09 (n=10)] groups developed aneurysms at 4 and 8 weeks compared with their respective controls ( P −/− animals developed larger aneurysms than the corresponding wild-type group ( P −/− group were larger at 8 weeks than at 4 weeks ( P −/− group compared with wild-type. Conclusions— Deletion of the TIMP-1 gene results in increased and continued progression of aneurysm formation compared with wild-type mice in a unique TAA model caused at least in part by an alteration in the balance between gelatinase activity and its endogenous inhibition. Therapeutic strategies aimed at modifying MMP activity may reduce or prevent the progression of TAAs.

Extracellular protease activation and unraveling of the myocardial interstitium: critical steps toward clinical applications

Abstract: Congestive heart failure is a complex pathophysiological process in which a significant biological underpinning is left ventricular (LV) failure. Part of the natural advancement to failure is myocardial remodeling, most commonly from adaptation to a pathological stimulus. LV remodeling can be

Myocardial remodeling after discrete radiofrequency injury: effects of tissue inhibitor of matrix metalloproteinase-1 gene deletion

Abstract: Discrete myocardial lesions created through the delivery of radiofrequency (RF) energy can expand; however, the mechanisms have not been established. Matrix metalloproteinases (MMPs) play an import...

Cell–Matrix Signaling and Thrombospondin Another Link to Myocardial Matrix Remodeling

Abstract: See related article, pages 515–522 Thrombospondins (TSP) are a family of secreted glycoproteins that participate in cell-to-matrix communication through a number of different pathways.1–8 Although TSP were first identified as a protein released by platelets after exposure to thrombin (hence the origin of the name of this family of proteins), it is now recognized that TSP are released by a number of cell types. TSP are secreted into the extracellular matrix (ECM) and interact with a number of important bioactive molecules, such as transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF).1,2,4,9,10 In general terms, TSP appear to modulate cell/matrix interactions through the coalescence of membrane proteins and signaling molecules at specific contact points on the cell surface.1,2,5,6 These sites of TSP/protein interactions at the cell surface, which then induce intracellular signaling events, include the integrins as well as integrin-associated proteins such as CD36 and CD47. Although 5 members of the TSP family exist, the best-studied are TSP-1 and TSP-2. The biological properties of TSP-1 and TSP-2 appear to be similar in general terms, but there are structural differences in TSP-1 and TSP-2 that may impart some unique functions with respect to cell-matrix signaling.11–14 In this issue, Schroen et al report a potential role of myocardial TSP-2 in the adaptive and maladaptive remodeling that occurs in left ventricular hypertrophy (LVH).15 To place the findings of this study in context with emerging studies regarding myocardial ECM remodeling and the progression to LV failure, a brief review of the biology of TSP with respect to matrix signaling and remodeling is presented here. One of the more established functions of TSP-1, and likely that of TSP-2, is to proteolytically process latent TGF-β to an active form.1,2,9 Through fusion protein studies and the development of a TSP-1 null …

The effects of leukocyte reduction on matrix metalloproteinase release in cardiopulmonary bypass.

Abstract: Matrix metalloproteinases (MMPs) are a family of enzymes responsible for degrading the extracellular matrix, a process that likely contributes to the development of altered vascular permeability. Past studies in patients undergoing cardiopulmonary bypass (CPB) have documented increased levels of MMPs with CPB. The purpose of this study was to evaluate the effect of leukocyte reduction on MMP release during CPB. Patients (n = 17) undergoing elective coronary revascularization requiring CPB were randomly assigned to either a leukocyte-reducing filter (LRF) group (n = 9) or the standard CPB circuit with no LRF (n = 8). White blood cell (WBC) counts, MMP-2, and MMP-9 levels were serially measured at baseline and up to 12 hours post CPB. MMP levels were measured by enzyme-linked immunoassay. ProMMP-2 levels increased in both the non-LRF and LRF groups but to a higher degree in the LRF group. ProMMP-9 levels increased by 40% in the non-LRF group. In contrast, proMMP-9 decreased by 30% in the LRF group. The addition of leukocyte-reducing filters in the CPB circuit attenuated the release of MMP-9 but increased release of MMP-2 post-CPB. Because MMPs can degrade the extracellular matrix, leading to increased vascular permeability, attenuation of MMPs may have decreased the local tissue injury known to occur as a result of these enzymes. However, future prospective studies to test this hypothesis directly are warranted.

Caspase inhibition attenuates contractile dysfunction following cardioplegic arrest and rewarming in the setting of left ventricular failure.

Abstract: :Hyperkalemic cardioplegic arrest (HCA) and rewarming evokes postoperative myocyte contractile dysfunction, a phenomenon of particular importance in settings of preexisting left ventricular (LV) failure. Caspases are intracellular proteolytic enzymes recently demonstrated to degrade myocardi

Introduction to Special Issue on The Matrix Metalloproteinases: New Insights into Myocardial Remodeling

Abstract: The LV myocardial remodeling process that invariably occurs during the progression of congestive heart failure (CHF) has historically been attributed to intrinsic changes in the cardiac myocyte. However, it is now recognized that important changes also occur within the extracellular matrix (ECM) of the myocardium, which contribute to, or may actually facilitate the remodeling process. The ECM is not a static entity, but rather contains a wide array of a structural proteins such as collagens, macromolecules such as proteoglycans and glycosaminoglycans, and serves as an important reservoir for bioactive signaling molecules. The myocardial collagens such as collagen types I and III, ensure structural integrity of adjoining myocytes, provide the means by which myocyte shortening is translated into overall LV pump function and are essential for maintaining alignment of myofibrils within the myocyte. Disruption or discontinuities within the fibrillar ECM network will result in a loss of normal structural support and continuity, resulting in myocyte fascicles being subjected to abnormal stress and strain patterns during the cardiac cycle, which in turn would result in changes in myocardial geometry and function. Alterations in basement membrane components and other macromolecules will significantly affect cell-cell interactions and material properties of the myocardium. Finally, changes in the structure and composition of interstitial proteins will influence receptor signaling through direct modifications on extracellular receptor domains as well as influencing relative levels of bioactive molecules within the extracellular space. Thus, the identification and understanding of the enzyme systems responsible for alterations in myocardial ECM structure and composition hold particular relevance with respect to LV remodeling and the progression to CHF. Over the past decade, significant research has been put forth to understand a family of proteolytic enzymes which have been identified within the myocardium and likely contribute to ECM remodeling and the progression to CHF: the matrix metalloproteinases (MMPs). The purpose of the focused series of reviews provided in this edition of Heart Failure Reviews are 3-fold. First, to summarize what is known regarding MMPs in animal models of LV remodeling. Second, to identify upstream pathways which likely contribute to the induction and alteration in myocardial MMP expression. Third, to examine potential pharmacological strategies which provided for a cause-effect relationship between MMP induction and myocardial remodeling as well as present a critical appraisal of clinical applications which arose from these basic studies. In the first article, Janicki and colleagues review the changes in relative myocardial MMP levels and activity which occur in several animal systems of myocardial remodeling: volume overload, pressure overload and myocardial infarction (MI). The authors emphasize several important points in this review with respect to MMPs and myocardial remodeling. First, that the temporal pattern of MMP activation is unique to the type of pathological stimulus. Second, that increased MMP levels appear to occur during maladaptive remodelingor decompensation to CHF. Finally, these investigators review data which support the functional role of changes in MMP abundance and activity with respect to indices of LV function. The second contribution in this series by M. Lindsey continues on the theme of MMP expression and activation in myocardial remodeling, but focuses more carefully on this process postMI. As detailed in this particular contribution, an area of intensive investigation is to identify the basis for heightened MMP activation which has been clearly demonstrated to cause adverse LV remodeling post-MI. This review emphasizes the importance of understanding which MMP types are responsible for adverse LV remodeling postMI as well as potential future research directions in this regard. The third review provided by Pauschinger and colleagues defines the role of the inflammatory process to herald in a cycle of MMP induction/activation which eventually gives rise to LV failure. To illustrate this point, the authors describe studies performed in a murine myocarditis model. The authors also emphasize that a continuous interaction exists within the myocardial interstitium with respect to signaling molecules which reduce MMP activity (thereby facilitating ECM accumulation) and those which increase MMP activity (thereby facilitating ECM degradation