Collagen matricryptin promotes cardiac function by mediating scar formation.

Aims: A peptide mimetic of a collagen-derived matricryptin (p1159) was shown to reduce left ventricular (LV) dilation and fibrosis after 7 days delivery in a mouse model of myocardial infarction (MI). This suggested p1159 long-term treatment post-MI could have beneficial effects and reduce/prevent adverse LV remodeling. This study aimed to test the potential of p1159 to reduce adverse cardiac remodeling in a chronic MI model and to elucidate p1159 mode-of-action.

Dopamine receptor D3 agonist (Pramipexole) reduces morphine-induced cardiac fibrosis.

Morphine is routinely used for pain management in heart failure patients. However, extended morphine exposure associates with major adverse cardiovascular events. Reports link the dopamine receptor D2-family with morphine-induced nociception modulation.

Age- and sex-dependent differences in extracellular matrix metabolism associate with cardiac functional and structural changes.

Age-related remodeling of the heart causes structural and functional changes in the left ventricle (LV) that are associated with a high index of morbidities and mortality worldwide. Some cardiac pathologies in the elderly population vary between genders revealing that cardiac remodeling during aging may be sex-dependent. Herein, we analyzed the effects of cardiac aging in male and female C57Bl/6 mice in four age groups, 3, 6, 12, and 18 month old (n = 6-12 animals/sex/age), to elucidate which age-related characteristics of LV remodeling are sex-specific.

Exogenous CXCL4 infusion inhibits macrophage phagocytosis by limiting CD36 signalling to enhance post-myocardial infarction cardiac dilation and mortality.

Aims: Macrophage phagocytosis of dead cells is a prerequisite for inflammation resolution. Because CXCL4 induces macrophage phagocytosis in vitro, we examined the impact of exogenous CXCL4 infusion on cardiac wound healing and macrophage phagocytosis following myocardial infarction (MI).

Methods And Results: CXCL4 expression significantly increased in the infarct region beginning at Day 3 post-MI, and macrophages were the predominant source.

The Mouse Heart Attack Research Tool 1.0 database.

The generation of big data has enabled systems-level dissections into the mechanisms of cardiovascular pathology. Integration of genetic, proteomic, and pathophysiological variables across platforms and laboratories fosters discoveries through multidisciplinary investigations and minimizes unnecessary redundancy in research efforts. The Mouse Heart Attack Research Tool (mHART) consolidates a large data set of over 10 yr of experiments from a single laboratory for cardiovascular investigators to generate novel hypotheses and identify new predictive markers of progressive left ventricular remodeling after myocardial infarction (MI) in mice.

Macrophage overexpression of matrix metalloproteinase-9 in aged mice improves diastolic physiology and cardiac wound healing after myocardial infarction.

Matrix metalloproteinase (MMP)-9 increases in the myocardium with advanced age and after myocardial infarction (MI). Because young transgenic (TG) mice overexpressing human MMP-9 only in macrophages show better outcomes post-MI, whereas aged TG mice show a worse aging phenotype, we wanted to evaluate the effect of aging superimposed on MI to see if the detrimental effect of aging counteracted the benefits of macrophage MMP-9 overexpression. We used 17- to 28-mo-old male and female C57BL/6J wild-type (WT) and TG mice ( n = 10-21 mice/group) to evaluate the effects of aging superimposed on MI.

Periodontal-induced chronic inflammation triggers macrophage secretion of Ccl12 to inhibit fibroblast-mediated cardiac wound healing.

Chronic inflammatory diseases, such as periodontal disease, associate with adverse wound healing in response to myocardial infarction (MI). The goal of this study was to elucidate the molecular basis for impaired cardiac wound healing in the setting of periodontal-induced chronic inflammation. Causal network analysis of 168 inflammatory and extracellular matrix genes revealed that chronic inflammation induced by a subseptic dose of Porphyromonas gingivalis lipopolysaccharide (LPS) exacerbated infarct expression of the proinflammatory cytokine Ccl12.

IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation.

Inflammation resolution is important for scar formation following myocardial infarction (MI) and requires the coordinated actions of macrophages and fibroblasts. In this study, we hypothesized that exogenous interleukin-10 (IL-10), an anti-inflammatory cytokine, promotes post-MI repair through actions on these cardiac cell types. To test this hypothesis, C57BL/6J mice (male, 3- to 6-month old, n = 24/group) were treated with saline or IL-10 (50 μg/kg/day) by osmotic mini-pump infusion starting at day (d) 1 post-MI and sacrificed at d7 post-MI.

Cardiac Fibroblast Activation Post-Myocardial Infarction: Current Knowledge Gaps.

In response to myocardial infarction (MI), the wound healing response of the left ventricle (LV) comprises overlapping inflammatory, proliferative, and maturation phases, and the cardiac fibroblast is a key cell type involved in each phase. It has recently been appreciated that, early post-MI, fibroblasts transform to a proinflammatory phenotype and secrete cytokines and chemokines as well as matrix metalloproteinases (MMPs). Later post-MI, fibroblasts are activated to anti-inflammatory and proreparative phenotypes and generate anti-inflammatory and proangiogenic factors and extracellular matrix (ECM) components that form the infarct scar.

Transgenic overexpression of macrophage matrix metalloproteinase-9 exacerbates age-related cardiac hypertrophy, vessel rarefaction, inflammation, and fibrosis.

Advancing age is an independent risk factor for cardiovascular disease. Matrix metalloproteinase-9 (MMP-9) is secreted by macrophages and robustly increases in the left ventricle (LV) with age. The present study investigated the effect of MMP-9 overexpression in macrophages on cardiac aging.

Early matrix metalloproteinase-9 inhibition post-myocardial infarction worsens cardiac dysfunction by delaying inflammation resolution.

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.

N-Glycosylation influences transport, but not cellular trafficking, of a neuronal amino acid transporter SNAT1.

SNAT1 is a system N/A neutral amino acid transporter that primarily expresses in neurons and mediates the transport of l-glutamine (Gln). Gln is an important amino acid involved in multiple cellular functions and also is a precursor for neurotransmitters, glutamate and GABA. In the present study, we demonstrated that SNAT1 is an N-glycoprotein expressed in neurons.

Defining the sham environment for post-myocardial infarction studies in mice.

The purpose of this study was to evaluate the effect of sham surgery in a minimally invasive surgical model of permanent coronary artery occlusion used to generate myocardial infarction (MI) in mice. Adult male C57BL/6J mice (3-6 mo old) were divided into five groups: day (D) 0 (no surgical operation), D1 Sham, D1 MI, D7 Sham, and D7 MI. A refined MI surgery technique was used to approach the coronary artery without the ribs being cut.

MMP-9 signaling in the left ventricle following myocardial infarction.

Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of cardiac wound healing responses that involve both the stimulation of robust inflammation to clear necrotic myocytes and tissue debris and the induction of extracellular matrix (ECM) protein synthesis to generate an infarct scar. The collective changes in myocardial structure and function are termed LV remodeling, and matrix metalloproteinase-9 (MMP-9) is a key instigator of post-MI LV remodeling. Through direct molecular effects on ECM and inflammatory protein turnover as well as indirect effects on major cell types that coordinate cardiac wound healing, namely the infiltrating leukocytes and the cardiac fibroblasts, MMP-9 coordinates multiple aspects of LV remodeling.

Temporal neutrophil polarization following myocardial infarction.

Aims: Although macrophage phenotypes have been well studied in the myocardial infarction (MI) setting, this study investigated temporal neutrophil polarization and activation mechanisms.

Methods And Results: Neutrophils isolated from the infarcted left ventricle (LV) of mice showed high expression of proinflammatory markers at Day 1 and anti-inflammatory markers at Days 5 and 7 post-MI, indicating distinct neutrophil phenotypes along the post-MI time continuum. Flow cytometry analysis revealed that although proinflammatory N1 neutrophils were always predominant (>80% of total neutrophils at each time point), the percentage of N2 neutrophils increased post-MI from 2.

Matrix metalloproteinases as input and output signals for post-myocardial infarction remodeling.

Despite current optimal therapeutic regimens, approximately one in four patients diagnosed with myocardial infarction (MI) will go on to develop congestive heart failure, and heart failure has a high five-year mortality rate of 50%. Elucidating mechanisms whereby heart failure develops post-MI, therefore, is highly needed. Matrix metalloproteinases (MMPs) are key enzymes involved in post-MI remodeling of the left ventricle (LV).

CD36 Is a Matrix Metalloproteinase-9 Substrate That Stimulates Neutrophil Apoptosis and Removal During Cardiac Remodeling.

Background: After myocardial infarction, the left ventricle undergoes a wound healing response that includes the robust infiltration of neutrophils and macrophages to facilitate removal of dead myocytes as well as turnover of the extracellular matrix. Matrix metalloproteinase (MMP)-9 is a key enzyme that regulates post-myocardial infarction left ventricular remodeling.

Methods And Results: Infarct regions from wild-type and MMP-9 null mice (n=8 per group) analyzed by glycoproteomics showed that of 541 N-glycosylated proteins quantified, 45 proteins were at least 2-fold upregulated or downregulated with MMP-9 deletion (all P<0.

A Novel Collagen Matricryptin Reduces Left Ventricular Dilation Post-Myocardial Infarction by Promoting Scar Formation and Angiogenesis.

Background: Proteolytically released extracellular matrix (ECM) fragments, matricryptins, are biologically active and play important roles in wound healing. Following myocardial infarction (MI), collagen I, a major component of cardiac ECM, is cleaved by matrix metalloproteinases (MMPs).

Objectives: This study identified novel collagen-derived matricryptins generated post-MI that mediate remodeling of the left ventricle (LV).

Building a better infarct: Modulation of collagen cross-linking to increase infarct stiffness and reduce left ventricular dilation post-myocardial infarction.

Matrix metalloproteinase-9 (MMP-9) deletion attenuates collagen accumulation and dilation of the left ventricle (LV) post-myocardial infarction (MI); however the biomechanical mechanisms underlying the improved outcome are poorly understood. The aim of this study was to determine the mechanisms whereby MMP-9 deletion alters collagen network composition and assembly in the LV post-MI to modulate the mechanical properties of myocardial scar tissue. Adult C57BL/6J wild-type (WT; n=88) and MMP-9 null (MMP-9(-/-); n=92) mice of both sexes underwent permanent coronary artery ligation and were compared to day 0 controls (n=42).

Early matrix metalloproteinase-12 inhibition worsens post-myocardial infarction cardiac dysfunction by delaying inflammation resolution.

Rationale: Matrix metalloproteinases (MMPs) regulate remodeling of the left ventricle (LV) post-myocardial infarction (MI). MMP-12 has potent macrophage-dependent remodeling properties in the atherosclerotic plaque; however, post-MI roles have not been examined.

Objective: The goal was to determine MMP-12 post-MI mechanisms.

Using the laws of thermodynamics to understand how matrix metalloproteinases coordinate the myocardial response to injury.

Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of molecular, cellular, and functional alterations that are both part of the wound healing response to form a scar in the infarct region and the consequence of that response. Using the laws of thermodynamics as an analogy, we present here three laws for categorizing the post-MI LV remodeling process. The first law is that the LV will attempt to maintain equilibrium and compensate as a way to maximize function, the second law is that remodeling is progressive and unidirectional, and the third law is that the final goal is (ideally, but not always achievable) a stable, equilibrated scar.

P. gingivalis lipopolysaccharide intensifies inflammation post-myocardial infarction through matrix metalloproteinase-9.

Periodontal disease (PD) strongly correlates with increased mortality post-myocardial infarction (MI); however, the underlying mechanisms are unknown. Matrix metalloproteinase (MMP)-9 levels directly correlate with dysfunction and remodeling of the left ventricle (LV) post-MI. Post-MI, MMP-9 is produced by leukocytes and modulates inflammation.

Aliskiren and valsartan mediate left ventricular remodeling post-myocardial infarction in mice through MMP-9 effects.

We evaluated whether aliskiren, valsartan, or a combination of both was protective following myocardial infarction (MI) through effects on matrix metalloproteinase (MMP)-9. C57BL/6J wild type (WT, n=94) and MMP-9 null (null, n=85) mice were divided into 4 groups at 3h post-MI: saline (S), aliskiren (A; 50mg/kg/day), valsartan (V; 40mg/kg/day), or A+V and compared to no MI controls at 28days post-MI. All groups had similar infarct areas, and survival rates were higher in the null mice.

Translating Koch's postulates to identify matrix metalloproteinase roles in postmyocardial infarction remodeling: cardiac metalloproteinase actions (CarMA) postulates.

The first matrix metalloproteinase (MMP) was described in 1962; and since the 1990s, cardiovascular research has focused on understanding how MMPs regulate many aspects of cardiovascular pathology from atherosclerosis formation to myocardial infarction and stroke. Although much information has been gleaned by these past reports, to a large degree MMP cardiovascular biology remains observational, with few studies homing in on cause and effect relationships. Koch's postulates were first developed in the 19th century as a way to establish microorganism function and were modified in the 20th century to include methods to establish molecular causality.

Myofibroblasts and the extracellular matrix network in post-myocardial infarction cardiac remodeling.

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.