Aging reveals a sex-dependent susceptibility of sarcospan-deficient mice to cardiometabolic disease.

Numerous genes including sarcospan (SSPN) have been designated as obesity-susceptibility genes by human genome-wide association studies. Variants in the locus have been linked with sex-dependent obesity-associated traits; however, this association has not been investigated in vivo. To delineate the role SSPN plays in regulating metabolism with potential to impact cardiac function, we subjected young and aged global SSPN-deficient (SSPN) male and female mice to obesogenic conditions (60% fat diet).

Sarcospan Deficiency Increases Oxidative Stress and Arrhythmias in Hearts after Acute Ischemia-Reperfusion Injury.

The protein sarcospan (SSPN) is an integral member of the dystrophin-glycoprotein complex (DGC) and has been shown to be important in the heart during the development and the response to acute stress. In this study, we investigated the role of SSPN in the cardiac response to acute ischemia-reperfusion (IR) injury in SSPN-deficient (SSPN) mice. First, the hemodynamic response of SSPN mice was tested and was similar to SSPN (wild-type) mice after isoproterenol injection.

Ovariectomy aggravates the pathophysiological response to exertional heat stroke in mice.

Female mice have a greater capacity for exercising in the heat than male mice, reaching greater power output and longer times of heat exposure before succumbing to exertional heat stroke (EHS). Differences in body mass, size, or testosterone do not explain these distinct sex responses. Whether the ovaries could account for the superior exercise capacity in the heat in females remains unknown.

Autoimmunity as a sequela to obesity and systemic inflammation.

The rising prevalence of obesity presents a world-wide challenge as it is associated with numerous comorbidities including cardiovascular disease, insulin resistance and hypertension. Obesity-associated illnesses are estimated to cause nearly 4 million deaths globally per year, therefore there is a critical need to better understand associated pathogenesis, identify new therapeutic targets, and develop new interventions. Emerging data identify a key role for chronic inflammation in mediating obesity related disease states and reveal higher incidence of autoimmune disease development.

The impact of hindlimb disuse on sepsis-induced myopathy in mice.

Sepsis induces a myopathy characterized by loss of muscle mass and weakness. Septic patients undergo prolonged periods of limb muscle disuse due to bed rest. The contribution of limb muscle disuse to the myopathy phenotype remains poorly described.

Anomalous structural dynamics of minimally frustrated residues in cardiac troponin C triggers hypertrophic cardiomyopathy.

Cardiac TnC (cTnC) is highly conserved among mammals, and genetic variants can result in disease by perturbing Ca-regulation of myocardial contraction. Here, we report the molecular basis of a human mutation in cTnC's αD-helix (-p.C84Y) that impacts conformational dynamics of the D/E central-linker and sampling of discrete states in the N-domain, favoring the "primed" state associated with Ca binding.

Cardiovascular Injury Due to SARS-CoV-2.

Purpose Of Review: The world is currently facing the largest global health crisis since the early 1900s due to a novel . While SARS-CoV-2 infection causes predictable symptoms in COVID-19 patients, including upper respiratory distress and fever, the heterogeneity of manifestations is surprising. This review focuses on direct and indirect causes of myocardial injury in COVID-19 patients and highlights current knowledge, treatment strategies, and outstanding questions in the field.

Essential roles of the dystrophin-glycoprotein complex in different cardiac pathologies.

The dystrophin-glycoprotein complex (DGC), situated at the sarcolemma dynamically remodels during cardiac disease. This review examines DGC remodeling as a common denominator in diseases affecting heart function and health. Dystrophin and the DGC serve as broad cytoskeletal integrators that are critical for maintaining stability of muscle membranes.

Anti-vinculin antibodies in scleroderma (SSc): a potential link between autoimmunity and gastrointestinal system involvement in two SSc cohorts.

Background: Systemic sclerosis (SSc) is an autoimmune disorder and commonly presents with vascular system involvement and motility disorders in the gastrointestinal (GI) tract. Vinculin is a cytoskeletal protein that plays major roles in cell-cell adhesion and is expressed in the neuromuscular apparatus of the gut. Antibodies to vinculin have been identified as a biomarker of irritable bowel syndrome (IBS).

Sexual dimorphism in cardiac transcriptome associated with a troponin C murine model of hypertrophic cardiomyopathy.

Heart disease remains the number one killer of women in the US. Nonetheless, studies in women and female animal models continue to be underrepresented in cardiac research. Hypertrophic cardiomyopathy (HCM), the most commonly inherited cardiac disorder, has been tied to sarcomeric protein variants in both sexes.

pDCs in lung and skin fibrosis in a bleomycin-induced model and patients with systemic sclerosis.

Fibrosis is the end result of most inflammatory conditions, but its pathogenesis remains unclear. We demonstrate that, in animals and humans with systemic fibrosis, plasmacytoid DCs (pDCs) are unaffected or are reduced systemically (spleen/peripheral blood), but they increase in the affected organs (lungs/skin/bronchoalveolar lavage). A pivotal role of pDCs was shown by depleting them in vivo, which ameliorated skin and/or lung fibrosis, reduced immune cell infiltration in the affected organs but not in spleen, and reduced the expression of genes and proteins implicated in chemotaxis, inflammation, and fibrosis in the affected organs of animals with bleomycin-induced fibrosis.

Eicosanoids in the innate immune response: TLR and non-TLR routes.

The variable array of pattern receptor expression in different cells of the innate immune system explains the induction of distinct patterns of arachidonic acid (AA) metabolism. Peptidoglycan and mannan were strong stimuli in neutrophils, whereas the fungal extract zymosan was the most potent stimulus in monocyte-derived dendritic cells since it induced the production of PGE(2), PGD(2), and several cytokines including a robust IL-10 response. Zymosan activated kappaB-binding activity, but inhibition of NF-kappaB was associated with enhanced IL-10 production.

Costimulation of dectin-1 and DC-SIGN triggers the arachidonic acid cascade in human monocyte-derived dendritic cells.

Inflammatory mediators derived from arachidonic acid (AA) alter the function of dendritic cells (DC), but data regarding their biosynthesis resulting from stimulation of opsonic and nonopsonic receptors are scarce. To address this issue, the production of eicosanoids by human monocyte-derived DC stimulated via receptors involved in Ag recognition was assessed. Activation of FcgammaR induced AA release, short-term, low-grade PG biosynthesis, and IL-10 production, whereas zymosan, which contains ligands of both the mannose receptor and the human beta-glucan receptor dectin-1, induced a wider set of responses including cyclooxygenase 2 induction and biosynthesis of leukotriene C(4) and IL-12p70.

Mannan and peptidoglycan induce COX-2 protein in human PMN via the mammalian target of rapamycin.

The induction of cyclooxygenase-2 (COX-2) protein expression was assessed in human polymorphonuclear leukocytes (PMN) stimulated via receptors of the innate immune system. Peptidoglycan (PGN) and mannan, and at a lower extent the bacterial lipoprotein mimic palmitoyl-3-cysteine-serine-lysine-4, induced COX-2 protein expression. In contrast, lipoteichoic acid and muramyldipeptide were irrelevant stimuli.

Peptidoglycan and mannose-based molecular patterns trigger the arachidonic acid cascade in human polymorphonuclear leukocytes.

The release of arachidonic acid (AA) in response to microorganism-derived products acting on pattern recognition receptors (PRR) was assayed in human polymorphonuclear leukocytes (PMN). Peptidoglycan (PGN) and mannan were found to be strong inducers of AA metabolism, as they produced the release of AA at a similar extent to that produced by agonists of pathophysiological relevance such as complement-coated zymosan particles and IgG immune complexes. In sharp contrast, lipoteichoic acid, LPS, muramyldipeptide, and the bacterial lipoprotein mimic palmitoyl-3-cysteine-serine-lysine-4 failed to do so.

Markers of inflammation before and after renal transplantation.

Background: This study aims to compare serum C-reactive protein (CRP), interleukin (IL-6), and tumor necrosis factor (TNF)-alpha in end-stage renal disease (ESRD) patients before versus after receiving renal transplantation (RT) and versus donors.

Methods: Serum samples from 37 ESRD patients (24 male, age 34+/-13 years) were collected before and after RT; in addition, samples from 31 donors were obtained at transplantation. CRP concentrations were measured using nephelometry, and TNF-alpha and IL-6 were measured by enzyme-linked immunoadsorbent assay.

Mannose-containing molecular patterns are strong inducers of cyclooxygenase-2 expression and prostaglandin E2 production in human macrophages.

The induction of cyclooxygenase-2 (COX-2) and the production of PGE(2) in response to pathogen-associated molecular patterns decorated with mannose moieties were studied in human monocytes and monocyte-derived macrophages (MDM). Saccharomyces cerevisiae mannan was a robust agonist, suggesting the involvement of the mannose receptor (MR). MR expression increased along the macrophage differentiation route, as judged from both its surface display assessed by flow cytometry and the ability of MDM to ingest mannosylated BSA.