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DeCoux A.,San Antonio Cardiovascular Proteomics Center | Lindsey M.L.,San Antonio Cardiovascular Proteomics Center | Villarreal F.,Bristol Myers Squibb | Garcia R.A.,University of California at San Diego | And 2 more authors.
Journal of Molecular and Cellular Cardiology | Year: 2014

Since their inaugural discovery in the early 1960s, matrix metalloproteinases (MMPs) have been shown to mediate multiple physiological and pathological processes. In addition to their canonical function in extracellular matrix (ECM) remodeling, research in the last decade has highlighted new MMP functions, including proteolysis of novel substrates beyond ECM proteins, MMP localization to subcellular organelles, and proteolysis of susceptible intracellular proteins in those subcellular compartments. This review will provide a comparison of the extracellular and intracellular roles of MMPs, illustrating that MMPs are far more interesting than the one-dimensional view originally taken. We focus on the roles of MMP-2 in cardiac injury and repair, as this is one of the most studied MMPs in the cardiovascular field. We will highlight how understanding all dimensions, such as localization of activity and timing of interventions, will increase the translational potential of research findings. Building upon old ideas and turning them inside out and upside down will help us to better understand how to move the MMP field forward. © 2014 Elsevier Ltd. Source

Xiao Y.,University of Texas at San Antonio | Xiao Y.,San Antonio Cardiovascular Proteomics Center | Hayman D.,University of Texas at San Antonio | Khalafvand S.S.,University of Texas at San Antonio | And 5 more authors.
American Journal of Physiology - Heart and Circulatory Physiology | Year: 2014

Tortuous carotid arteries are often seen in aged populations and are associated with atherosclerosis, but the underlying mechanisms to explain this preference are unclear. Artery buckling has been suggested as one potential mechanism for the development of tortuous arteries. The objective of this study, accordingly, was to determine the effect of buckling on cell proliferation and associated NF-κB activation in arteries. We developed a technique to generate buckling in porcine carotid arteries using long artery segments in organ culture without changing the pressure, flow rate, and axial stretch ratio. Using this technique, we examined the effect of buckling on arterial wall remodeling in 4-day organ culture under normal and hypertensive pressures. Cell proliferation, NF-κB p65, IκB-α, ERK1/2, and caspase-3 were detected using immunohistochemistry staining and immunoblot analysis. Our results showed that cell proliferation was elevated 5.8-fold in the buckling group under hypertensive pressure (n = 7, P < 0.01) with higher levels of NF-κB nuclear translocation and IκB-α degradation (P < 0.05 for both). Greater numbers of proliferating cells were observed on the inner curve side of the buckled arteries compared with the outer curve side (P < 0.01). NF-κB colocalized with proliferative nuclei. Computational simulations using a fluid-structure interaction model showed reduced wall stress on the inner side of buckled arteries and elevated wall stress on the outer side. We conclude that arterial buckling promotes site-specific wall remodeling with increased cell proliferation and NF-κB activation. These findings shed light on the biomechanical and molecular mechanisms of the pathogenesis of atherosclerosis in tortuous arteries. © 2014 the American Physiological Society. Source

Chiao Y.A.,San Antonio Cardiovascular Proteomics Center | Chiao Y.A.,Barshop Institute for Longevity and Aging Studies | Chiao Y.A.,University of Texas Health Science Center at San Antonio | Ramirez T.A.,San Antonio Cardiovascular Proteomics Center | And 17 more authors.
Cardiovascular Research | Year: 2012

AimsAge-related diastolic dysfunction has been attributed to an increased passive stiffness, which is regulated by extracellular matrix (ECM). We recently showed that matrix metalloproteinase (MMP)-9, an ECM mediator, increases in the left ventricle (LV) with age. The aim of this study, accordingly, was to determine the role of MMP-9 in cardiac ageing.Methods and resultsWe compared LV function in young (6-9 months), middle-aged (12-15 months), old (18-24 months) and senescent (26-34 months) wild-type (WT) and MMP-9 null mice (n ≥ 12/group). All groups had similar fractional shortenings and aortic peak velocities, indicating that systolic function was not altered by ageing or MMP-9 deletion. The mitral ratios of early to late diastolic filling velocities were reduced in old and senescent WT compared with young controls, and this reduction was attenuated in MMP-9 null mice. Concomitantly, the increase in LV collagen content was reduced in MMP-9 null mice (n = 5-6/group). To dissect the mechanisms of these changes, we evaluated the mRNA expression levels of 84 ECM and adhesion molecules by real-time qPCR (n = 6/group). The expression of pro-fibrotic periostin and connective tissue growth factor (CTGF) increased with senescence, as did transforming growth factor-β (TGF-β)-induced protein levels and Smad signalling, and these increases were blunted by MMP-9 deletion. In senescence, MMP-9 deletion also resulted in a compensatory increase in MMP-8.ConclusionMMP-9 deletion attenuates the age-related decline in diastolic function, in part by reducing TGF-β signalling-induced periostin and CTGF expression and increasing MMP-8 expression to regulate myocardial collagen turnover and deposition. © 2012 The Author. Source

Ma Y.,San Antonio Cardiovascular Proteomics Center | Ma Y.,University of Mississippi Medical Center | Yabluchanskiy A.,San Antonio Cardiovascular Proteomics Center | Yabluchanskiy A.,University of Mississippi Medical Center | And 3 more authors.
Fibrogenesis and Tissue Repair | Year: 2013

Polymorphonuclear granulocytes (PMNs; neutrophils) serve as key effector cells in the innate immune system and provide the first line of defense against invading microorganisms. In addition to producing inflammatory cytokines and chemokines and undergoing a respiratory burst that stimulates the release of reactive oxygen species, PMNs also degranulate to release components that kill pathogens. Recently, neutrophil extracellular traps have been shown to be an alternative way to trap microorganisms and contain infection. PMN-derived granule components are also involved in multiple non-infectious inflammatory processes, including the response to myocardial infarction (MI). In this review, we will discuss the biological characteristics, recruitment, activation, and removal of PMNs, as well as the roles of PMN-derived granule proteins in inflammation and innate immunity, focusing on the MI setting when applicable. We also discuss future perspectives that will direct research in PMN biology. © 2013 Ma et al.; licensee BioMed Central Ltd. Source

Ma Y.,San Antonio Cardiovascular Proteomics Center | Ma Y.,University of Mississippi Medical Center | De Castro Bras L.E.,San Antonio Cardiovascular Proteomics Center | De Castro Bras L.E.,University of Mississippi Medical Center | And 15 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2014

The cardiac extracellular matrix (ECM) fills the space between cells, supports tissue organization, and transduces mechanical, chemical, and biological signals to regulate homeostasis of the left ventricle (LV). Following myocardial infarction (MI), a multitude of ECM proteins are synthesized to replace myocyte loss and form a reparative scar. Activated fibroblasts (myofibroblasts) are the primary source of ECM proteins, thus playing a key role in cardiac repair. A balanced turnover of ECM through regulation of synthesis by myofibroblasts and degradation by matrix metalloproteinases (MMPs) is critical for proper scar formation. In this review, we summarize the current literature on the roles of myofibroblasts, MMPs, and ECM proteins in MI-induced LV remodeling. In addition, we discuss future research directions that are needed to further elucidate the molecular mechanisms of ECM actions to optimize cardiac repair. © 2014 The Author(s). Source

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