Increased ADAMTS1 mediates SPARC-dependent collagen deposition in the aging myocardium.

Secreted protein acidic and rich in cysteine (SPARC) is a collagen-binding matricellular protein highly expressed during fibrosis. Fibrosis is a prominent component of cardiac aging that reduces myocardial elasticity. Previously, we reported that SPARC deletion attenuated myocardial stiffness and collagen deposition in aged mice.

The impact of intolerance of emotional distress and uncertainty on veterans with co-occurring PTSD and substance use disorders.

The risk of developing a substance use disorder (SUD) is significantly higher among veterans with posttraumatic stress disorder (PTSD). Veterans with this co-occurrence have poorer outcomes than singly diagnosed veterans, which may be related to two risk factors: intolerance uncertainty (IU) and low tolerance of emotional distress (TED). We hypothesized low TED and high IU would independently and interactively relate to heightened PTSD symptomatology and trauma-cue elicited SUD cravings.

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.

The crossroads of inflammation, fibrosis, and arrhythmia following myocardial infarction.

Optimal healing of damaged tissue following myocardial infarction (MI) requires a coordinated cellular response that can be divided into three phases: inflammatory, proliferative/reparative, and maturation. The inflammatory phase, characterized by rapid influx of cytokines, chemokines, and immune cells, is critical to the removal of damaged tissue. The onset of the proliferative/reparative phase is marked by increased proliferation of myofibroblasts and secretion of collagen to replace dead tissue.

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.

Normoaldosteronemic aldosterone-producing adenoma: immunochemical characterization and diagnostic implications.

Background: A high aldosterone-renin ratio (ARR) is commonly used to identify primary aldosteronism, but the ARR is high when renin is low, even if plasma aldosterone concentration values are normal, suggesting the existence of 'normoaldosteronemic' primary aldosteronism. However, most such cases did not undergo adrenalectomy; moreover, because of the lack of antibody for the human CYP11B2 (aldosterone synthase), conclusive demonstration of a normoaldosteronemic aldosterone-producing adenoma was not possible thus far.

Method: In 2003, a lady presented with severe hypertension a right adrenal nodule, low renin, high ARR, but normal plasma aldosterone concentration.

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).

The circular relationship between matrix metalloproteinase-9 and inflammation following myocardial infarction.

Matrix metalloproteinase-9 (MMP-9) regulates remodeling of the left ventricle after myocardial infarction (MI) and is tightly linked to the inflammatory response. The inflammatory response serves to recruit leukocytes as part of the wound healing reaction to the MI injury, and infiltrated leukocytes produce cytokines and chemokines that stimulate MMP-9 production and release. In turn, MMP-9 proteolyzes cytokines and chemokines.

Aldosterone-stimulating somatic gene mutations are common in normal adrenal glands.

Primary aldosteronism (PA) represents the most common cause of secondary hypertension, but little is known regarding its adrenal cellular origins. Recently, aldosterone-producing cell clusters (APCCs) with high expression of aldosterone synthase (CYP11B2) were found in both normal and PA adrenal tissue. PA-causing aldosterone-producing adenomas (APAs) harbor mutations in genes encoding ion channels/pumps that alter intracellular calcium homeostasis and cause renin-independent aldosterone production through increased CYP11B2 expression.

Osteopontin is proteolytically processed by matrix metalloproteinase 9.

Osteopontin is robustly upregulated following myocardial infarction (MI), which suggests that it has an important role in post-MI remodeling of the left ventricle (LV). Osteopontin deletion results in increased LV dilation and worsened cardiac function. Thus, osteopontin exerts protective effects post-MI, but the mechanisms have yet to be defined.

Role of Nongenomic Signaling Pathways Activated by Aldosterone During Cardiac Reperfusion Injury.

Aldosterone (Aldo) activates both genomic and nongenomic signaling pathways in the cardiovascular system. Activation of genomic signaling pathways contributes to the adverse cardiac actions of Aldo during reperfusion injury; however, the extent nongenomic signaling pathways contribute has been difficult to identify due to lack of a specific ligand that activates only nongenomic signaling pathways. Using a pegylated aldosterone analog, aldosterone-3-carboxymethoxylamine-TFP ester conjugated to methoxypegylated amine (Aldo-PEG), we are able for the first time to distinguish between nongenomic and genomic cardiac actions of Aldo.

Plasma Glycoproteomics Reveals Sepsis Outcomes Linked to Distinct Proteins in Common Pathways.

Objective: Sepsis remains a predominant cause of mortality in the ICU, yet strategies to increase survival have proved largely unsuccessful. This study aimed to identify proteins linked to sepsis outcomes using a glycoproteomic approach to target extracellular proteins that trigger downstream pathways and direct patient outcomes.

Design: Plasma was obtained from the Lactate Assessment in the Treatment of Early Sepsis cohort.

Cardiac aging: Send in the vinculin reinforcements.

Integration of multiple analytical approaches across three species—fly, rat, and nonhuman primate—reveals additional roles for vinculin in cytoskeletal aging and cardiovascular disease (Kaushik et al., this issue).

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).

Deriving a cardiac ageing signature to reveal MMP-9-dependent inflammatory signalling in senescence.

Aims: Cardiac ageing involves the progressive development of cardiac fibrosis and diastolic dysfunction coordinated by MMP-9. Here, we report a cardiac ageing signature that encompasses macrophage pro-inflammatory signalling in the left ventricle (LV) and distinguishes biological from chronological ageing.

Methods And Results: Young (6-9 months), middle-aged (12-15 months), old (18-24 months), and senescent (26-34 months) mice of both C57BL/6J wild type (WT) and MMP-9 null were evaluated.

Myocardial Infarction Superimposed on Aging: MMP-9 Deletion Promotes M2 Macrophage Polarization.

In this study, we examined the combined effect of aging and myocardial infarction on left ventricular remodeling, focusing on matrix metalloproteinase (MMP)-9-dependent mechanisms. We enrolled 55 C57BL/6J wild type (WT) and 85 MMP-9 Null (Null) mice of both sexes at 11-36 months of age and evaluated their response at Day 7 post-myocardial infarction. Plasma MMP-9 levels positively linked to age in WT mice (r = .

Secreted protein acidic and rich in cysteine facilitates age-related cardiac inflammation and macrophage M1 polarization.

To investigate the role of secreted protein acidic and rich in cysteine (SPARC) in age-related cardiac inflammation, we studied six groups of mice: young (3-5 mo old), middle-aged (10-12 mo old), and old (18-29 mo old) C57BL/6 wild-type (WT) and SPARC-null (Null) mice (n = 7-10/group). Cardiac function and structure were determined by echocardiography. The left ventricle was used for cytokine gene array and macrophage quantification by immunohistochemistry.

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.

Interphotoreceptor retinoid-binding protein protects retinoids from photodegradation.

Retinol degrades rapidly in light into a variety of photoproducts. It is remarkable that visual cycle retinoids can evade photodegradation as they are exchanged between the photoreceptors, retinal pigment epithelium and Müller glia. Within the interphotoreceptor matrix, all-trans retinol, 11-cis retinol and retinal are bound by interphotoreceptor retinoid-binding protein (IRBP).

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.

Obesity superimposed on aging magnifies inflammation and delays the resolving response after myocardial infarction.

Polyunsaturated fatty acid (PUFA) intake has increased over the last 100 yr, contributing to the current obesogenic environment. Obesity and aging are prominent risk factors for myocardial infarction (MI). How obesity interacts with aging to alter the post-MI response, however, is unclear.