San Antonio Cardiovascular Proteomics Center

San Antonio, United States

San Antonio Cardiovascular Proteomics Center

San Antonio, United States
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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).

Ma Y.,San Antonio Cardiovascular Proteomics Center | Ma Y.,University of Texas Health Science Center at San Antonio | Halade G.V.,San Antonio Cardiovascular Proteomics Center | Halade G.V.,University of Texas Health Science Center at San Antonio | And 15 more authors.
Circulation Research | Year: 2013

Rationale: Matrix metalloproteinase (MMP)-28 regulates the inflammatory and extracellular matrix responses in cardiac aging, but the roles of MMP-28 after myocardial infarction (MI) have not been explored. Objective: To determine the impact of MMP-28 deletion on post-MI remodeling of the left ventricle (LV). Methods and Results: Adult C57BL/6J wild-type (n=76) and MMP null (MMP-28, n=86) mice of both sexes were subjected to permanent coronary artery ligation to create MI. MMP-28 expression decreased post-MI, and its cell source shifted from myocytes to macrophages. MMP-28 deletion increased day 7 mortality because of increased cardiac rupture post-MI. MMP-28 mice exhibited larger LV volumes, worse LV dysfunction, a worse LV remodeling index, and increased lung edema. Plasma MMP-9 levels were unchanged in the MMP-28 mice but increased in wild-type mice at day 7 post-MI. The mRNA levels of inflammatory and extracellular matrix proteins were attenuated in the infarct regions of MMP-28 mice, indicating reduced inflammatory and extracellular matrix responses. M2 macrophage activation was impaired when MMP-28 was absent. MMP-28 deletion also led to decreased collagen deposition and fewer myofibroblasts. Collagen cross-linking was impaired as a result of decreased expression and activation of lysyl oxidase in the infarcts of MMP-28 mice. The LV tensile strength at day 3 post-MI, however, was similar between the 2 genotypes. Conclusions: MMP-28 deletion aggravated MI-induced LV dysfunction and rupture as a result of defective inflammatory response and scar formation by suppressing M2 macrophage activation. © 2012 American Heart Association, Inc.

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.

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.

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.

Yabluchanskiy A.,San Antonio Cardiovascular Proteomics Center | Yabluchanskiy A.,University of Mississippi Medical Center | Ma Y.,San Antonio Cardiovascular Proteomics Center | Ma Y.,University of Mississippi Medical Center | And 7 more authors.
Physiology | Year: 2013

Matrix metalloproteinase (MMP)-9, one of the most widely investigated MMPs, regulates pathological remodeling processes that involve inflammation and fibrosis in cardiovascular disease. MMP-9 directly degrades extracellular matrix (ECM) proteins and activates cytokines and chemokines to regulate tissue remodeling. MMP-9 deletion or inhibition has proven overall beneficial in multiple animal models of cardiovascular disease. As such, MMP-9 expression and activity is a common end point measured. MMP-9 cell-specific overexpression, however, has also proven beneficial and highlights the fact that little information is available on the underlying mechanisms of MMP-9 function. In this review, we summarize our current understanding of MMP-9 physiology, including structure, regulation, activation, and downstream effects of increased MMP-9. We discuss MMP-9 roles during inflammation and fibrosis in cardiovascular disease. By concentrating on the substrates of MMP-9 and their roles in cardiovascular disease, we explore the overall function and discuss future directions on the translational potential of MMP-9 based therapies. © 2013 Int. Union Physiol. Sci./Am. Physiol. Soc.

Liu R.,University of Texas at San Antonio | Qian C.,University of Texas at San Antonio | Liu S.,Northwestern University | Jin Y.-F.,University of Texas at San Antonio | Jin Y.-F.,San Antonio Cardiovascular Proteomics Center
BMC Systems Biology | Year: 2016

Background: Driving Boolean networks to desired states is of paramount significance toward our ultimate goal of controlling the progression of biological pathways and regulatory networks. Despite recent computational development of controllability of general complex networks and structural controllability of Boolean networks, there is still a lack of bridging the mathematical condition on controllability to real boolean operations in a network. Further, no realtime control strategy has been proposed to drive a Boolean network. Results: In this study, we applied semi-tensor product to represent boolean functions in a network and explored controllability of a boolean network based on the transition matrix and time transition diagram. We determined the necessary and sufficient condition for a controllable Boolean network and mapped this requirement in transition matrix to real boolean functions and structure property of a network. An efficient tool is offered to assess controllability of an arbitrary Boolean network and to determine all reachable and non-reachable states. We found six simplest forms of controllable 2-node Boolean networks and explored the consistency of transition matrices while extending these six forms to controllable networks with more nodes. Importantly, we proposed the first state feedback control strategy to drive the network based on the status of all nodes in the network. Finally, we applied our reachability condition to the major switch of P53 pathway to predict the progression of the pathway and validate the prediction with published experimental results. Conclusions: This control strategy allowed us to apply realtime control to drive Boolean networks, which could not be achieved by the current control strategy for Boolean networks. Our results enabled a more comprehensive understanding of the evolution of Boolean networks and might be extended to output feedback control design. © 2016 The Author(s).

Ghasemi O.,University of Texas at San Antonio | Ghasemi O.,San Antonio Cardiovascular Proteomics Center | Ma Y.,San Antonio Cardiovascular Proteomics Center | Ma Y.,University of Mississippi Medical Center | And 5 more authors.
Wiley Interdisciplinary Reviews: Systems Biology and Medicine | Year: 2014

Inflammation and extracellular matrix (ECM) remodeling are important components regulating the response of the left ventricle to myocardial infarction (MI). Significant cellular- and molecular-level contributors can be identified by analyzing data acquired through high-throughput genomic and proteomic technologies that provide expression levels for thousands of genes and proteins. Large-scale data provide both temporal and spatial information that need to be analyzed and interpreted using systems biology approaches in order to integrate this information into dynamic models that predict and explain mechanisms of cardiac healing post-MI. In this review, we summarize the systems biology approaches needed to computationally simulate post-MI remodeling, including data acquisition, data analysis for biomarker classification and identification, data integration to build dynamic models, and data interpretation for biological functions. An example for applying a systems biology approach to ECM remodeling is presented as a reference illustration. © 2013 The Authors.

PubMed | Florida Atlantic University, University of Mississippi Medical Center, EMD Millipore, San Antonio Cardiovascular Proteomics Center and East Carolina University
Type: | Journal: Journal of molecular and cellular cardiology | Year: 2016

Matrix metalloproteinase-9 (MMP-9) is robustly elevated in the first week post-myocardial infarction (MI). Targeted deletion of the MMP-9 gene attenuates cardiac remodeling post-MI by reducing macrophage infiltration and collagen accumulation through increased apoptosis and reduced inflammation. In this study, we used a translational experimental design to determine whether selective MMP-9 inhibition early post-MI would be an effective therapeutic strategy in mice. We enrolled male C57BL/6J mice (3-6months old, n=116) for this study. Mice were subjected to coronary artery ligation. Saline or MMP-9 inhibitor (MMP-9i; 0.03g/day) treatment was initiated at 3h post-MI and the mice were sacrificed at day (D) 1 or 7 post-MI. MMP-9i reduced MMP-9 activity by 311% at D1 post-MI (p<0.05 vs saline) and did not affect survival or infarct area. Surprisingly, MMP-9i treatment increased infarct wall thinning and worsened cardiac function at D7 post-MI. While MMP-9i enhanced neutrophil infiltration at D1 and macrophage infiltration at D7 post-MI, CD36 levels were lower in MMP-9i compared to saline, signifying reduced phagocytic potential per macrophage. Escalation and prolongation of the inflammatory response at D7 post-MI in the MMP-9i group was evident by increased expression of 18 pro-inflammatory cytokines (all p<0.05). MMP-9i reduced cleaved caspase 3 levels at D7 post-MI, consistent with reduced apoptosis and defective inflammation resolution. Because MMP-9i effects on inflammatory cells were significantly different from previously observed MMP-9 null mechanisms, we evaluated pre-MI (baseline) systemic differences between C57BL/6J and MMP-9 null plasma. By mass spectrometry, 34 plasma proteins were significantly different between groups, revealing a previously unappreciated altered baseline environment pre-MI when MMP-9 was deleted. In conclusion, early MMP-9 inhibition delayed inflammation resolution and exacerbated cardiac dysfunction, highlighting the importance of using translational approaches in mice.

PubMed | University of Washington and San Antonio Cardiovascular Proteomics Center
Type: Journal Article | Journal: Proteomics. Clinical applications | Year: 2016

Matrix metalloproteinases (MMPs) collectively degrade all extracellular matrix (ECM) proteins. Of the MMPs, MMP-9 has the strongest link to the development of cardiac dysfunction. Aging associates with increased MMP-9 expression in the left ventricle (LV) and reduced cardiac function. We investigated the effect of MMP-9 deletion on the cardiac ECM in aged animals.We used male and female middle-aged (10- to16-month old) and old (20- to 24-month old) wild-type (WT) and MMP-9 null mice (n = 6/genotype/age). LVs were decellularized to remove highly abundant mitochondrial proteins that could mask identification of relative lower abundant components, analyzed by shotgun proteomics, and proteins of interest validated by immunoblot.Elastin microfibril interface-located protein 1 (EMILIN-1) decreased with age in WT (p < 0.05), but not in MMP-9 null. EMILIN-1 promotes integrin-dependent cell adhesion and EMILIN-1 deficiency has been associated with vascular stiffening. Talin-2, a cytoskeletal protein, was elevated with age in WT (p < 0.05), and MMP-9 deficiency blunted this increase. Talin-2 is highly expressed in adult cardiac myocytes, transduces mechanical force to the ECM, and is activated by increases in substrate stiffness. Our results suggest that MMP-9 deletion may reduce age-related myocardial stiffness, which may explain improved cardiac function in MMP-9 null animals.We identified age-related changes in the cardiac proteome that are MMP-9 dependent, suggesting MMP-9 as a possible therapeutic target for the aging patient.

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