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Fibroblast and Immune Cell Cross Talk in Cardiac Repair
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Stelios Psarras, Georgina Xanthou
In accordance with the pronounced heterogeneity and plasticity observed in fibro-blasts, ECM is also dynamically changing following cardiac injury. Collagens I and III are deposited to maintain cardiac tissue homeostasis, protecting from rupture post-MI but sustaining detrimental fibrosis in the long term. Other components, such as the proteoglycan agrin, support cardiac regeneration by promoting cardiomyocyte proliferation in the neonatal murine heart. Indeed, local agrin administration post-MI suppressed inflammation and fibrosis and improved cardiac function in preclinical models (47). Paradoxically, collagen V, a minor collagen species of the basement membrane upregulated upon MI injury, diminishes the infarct size by regulating fibroblast mechanosensing signaling in an integrin-dependent manner (48). The importance of ECM was clearly demonstrated in experiments in which decellularized ECM derived from regeneration-prone neonatal mouse hearts and injected into adult hearts alleviated cardiac dysfunction and scar expansion post-MI (49).
Proteinase Inhibitors: An Overview of their Structure and Possible Function in the Acute Phase
Published in Andrzej Mackiewicz, Irving Kushner, Heinz Baumann, Acute Phase Proteins, 2020
Four kazal families are known in mammals: the PSTI, submandibular inhibitor, seminal plasma inhibitor, and PEC-60 families. A recent report55 implicates the rat protein agrin as a multiheaded kazal. This protein, which causes aggregation of acetylcholine receptors on cultured muscle fibers, contains nine homologous repeats that have cysteine spacings close to that of a typical kazal domain55 (Figure 4). There is no evidence yet that the agrin segments have the kazal disulfide topology, nor whether some of them are proteinase inhibitors. Other mammalian kazals are not normally multiheaded (with the exception of the two-headed submandibular inhibitors), but nonmammalian vertebrates contain proteins that can have as many as seven tandem domains.1 Kazals are particularly rich in birds and reptiles, especially in their eggs, where they can account for a substantial portion of total protein.
Hematopoietic Stem Cell Therapy for Patients with Refractory Myasthenia Gravis
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
The diagnosis of MG is made by clinical manifestations, improvement to the anticholinesterase edrophonium chloride (Tensilon), and EMG. MG is characterized by weakness, often fluctuating, being worsened by exercise. Fatigue and weakness may occur in ocular, facial, bulbar, and/or limb muscles.9,10 Ocular ptosis, ophthalmoparesis, dysarthria, and dysphagia are common. In severe cases, respiratory muscles are affected. Electrophysiologic studies reveal loss of amplitude with repetitive nerve stimulation. Approximately 85% of patients with MG have anti-AChR antibodies. These patients may have other genetic or autoimmune-mediated problems with the nerve-muscle synapse. Achieving action potential threshold depends on clustering of the AChR at the motor endplate. A neuronal protein, agrin, activates muscle-specific kinase (MuSK) to cluster AChRs via rapsyn, a muscle cytoplasmic synapse protein (Fig. 1).24-26 Some MG patients without anti-AchR antibodies have antibodies to MuSK. Therefore, disruption of AChR clustering by either antibodies to AChR or MuSK results in the same clinical manifestations and EMG findings. MG must also be differentiated from other myasthenic syndromes such as Eaton Lambert syndrome, which is a malignancy-associated disorder with antibodies against PQ-type voltage-gated calcium channels.27 Eaton Lambert syndrome can be distinguished from MG by EMG.
Targeting the cytoskeleton and extracellular matrix in cardiovascular disease drug discovery
Published in Expert Opinion on Drug Discovery, 2022
Bohdan B. Khomtchouk, Yoon Seo Lee, Maha L. Khan, Patrick Sun, Deniel Mero, Michael H. Davidson
Agrin and spironolactone are two cardiac ECM-targeting drugs that strongly suggest that therapeutically modulating the ECM provides beneficial relevant CVD outcomes. Specifically, agrin is an ECM proteoglycan that causes the aggregation of acetylcholine receptors and is involved in the formation of the neuromuscular junction [128]. It has been shown to improve cardiac function after incidents of myocardial infarction and protection from DCM [128] Spironolactone, similarly, has shown beneficial effects of targeting the ECM in CVDs. Spironolactone limits ECM turnover and, therefore, decreases cardiac fibrosis [129]. It has improved outcomes of congestive HF patients along with lowering levels of cardiac fibrosis synthesis markers [129]. Studying these handful of current drugs and therapeutics that target the cytoskeleton/ECM and have also shown positive outcomes in CVDs strengthens the idea that the cellular architecture can provide a source of novel targets for drug development. However, there is the possible risk of a lack of specificity of targeting ECM proteins that may lead to adverse outcomes due to the fundamental roles that the extracellular matrix and the cytoskeleton play within our cells, but the previously discussed examples of drugs that target the ECM/cytoskeleton and have shown positive outcomes show us that this is still a field worth delving into especially when backed by computational analyses.
Increased levels of serum serglycin and agrin is associated with adverse perinatal outcome in early onset preeclampsia
Published in Fetal and Pediatric Pathology, 2019
Basak Gumus Guler, Sibel Ozler
Agrin is a proteoglycan located in the basal membrane and binds to laminin and integrin of ECM [12]. Agrin also interacts with the acetylcholine receptor and is involved in neuronal cell adhesion [21]. It is also expressed in fetal kidney and liver [21, 41] and causes lymphocyte activation via CD44 receptors [42, 43]. Vuades et al. observed increased agrin and perlecan levels in the amniotic fluid of preterm premature rupture of membrane (PPROM) patients when compared to their maternal serum levels, and suspected that agrin and perlecan were related to PPROM. These two proteins were found to be highly expressed in decidua and vessel walls of placental villi in PPROM patients [44]. Agrin was also shown to be expressed more in the placentas of diabetic patients when compared to the placentas of healthy term patients [12].
The extracellular matrix of the blood–brain barrier: structural and functional roles in health, aging, and Alzheimer’s disease
Published in Tissue Barriers, 2019
May J. Reed, Mamatha Damodarasamy, William A. Banks
The HSPGs found in BM are exemplified by perlecan and agrin, which promote barrier function. In the brain, HSPGs come from BEC, astrocytes and likely pericytes.93 Perlecan, also called HSPG2, is a large multidomain proteoglycan that binds to and cross-links other components of ECM, thereby stabilizing BM and ensuring maintenance of the endothelial barrier function.124 Less is known about agrin in aging and neurodegeneration. Agrin is also a large HSPG that has barrier functions and is found extensively in the basal lamina of the brain microvasculature.125 Agrin’s connection to the BM has been shown to be mediated by binding of its amino terminus with laminin.126