Cartilage oligomeric matrix protein is an endogenous β-arrestin-2-selective allosteric modulator of AT1 receptor counteracting vascular injury

AbstractCompelling evidence has revealed that biased activation of G protein-coupled receptor (GPCR) signaling, including angiotensin II (AngII) receptor type 1 (AT1) signaling, plays pivotal roles in vascular homeostasis and injury, but whether a clinically relevant endogenous biased antagonism of AT1 signaling exists under physiological and pathophysiological conditions has not been clearly elucidated. Here, we show that an extracellular matrix protein, cartilage oligomeric matrix protein (COMP), acts as an endogenous allosteric biased modulator of the AT1 receptor and its deficiency is clinically associated with abdominal aortic aneurysm (AAA) development. COMP directly interacts with the extracellular N-terminus of the AT1 via its EGF domain and inhibits AT1-β-arrestin-2 signaling, but not Gq or Gi signaling, in a selective manner through allosteric regulation of AT1 intracellular conformational states. COMP deficiency results in activation of AT1a-β-arrestin-2 signaling and subsequent exclusive AAA formation in response to AngII infusion. AAAs in COMP–/– or ApoE–/– mice are rescued by AT1a or β-arrestin-2 deficiency, or the application of a peptidomimetic mimicking the AT1-binding motif of COMP. Explorations of the endogenous biased antagonism of AT1 receptor or other GPCRs may reveal novel therapeutic strategies for cardiovascular diseases.

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D-Cell Hypothesis (Trace Amine Hypothesis) of Schizophrenia, and importance of Trace Amine-Associated Receptor, Type 1 (TAAR1)

Pharmacovigilance and Pharmacoepidemiology ◽

10.33805/2638-8235.102 ◽

2015 ◽

pp. 1-5

Author(s):

Keiko Ikemoto

Keyword(s):

Molecular Basis ◽

Therapeutic Strategies ◽

Immunohistochemical Method ◽

Trace Amine ◽

D Cell ◽

Postmortem Brains ◽

Novel Therapeutic Strategies ◽

D2 Antagonists ◽

Novel Therapeutic

Mesolimbic dopamine (DA) hyperactivity is a well-known pathophysiological hypothesis of schizophrenia. The author shows a hypothesis to clarify the molecular basis of mesolimbic DA hyperactivity of schizophrenia. An immunohistochemical method was used to show D-neuron (trace amine (TA) neuron) decrease in the nucleus accumbens (Acc) of postmortem brains with schizophrenia. The striatal D-neuron decrease in schizophrenia and consequent (TAAR1) stimulation decrease onto terminals of midbrain ventral tegmental area (VTA) DA neurons induces mesolimbic DA hyperactivity of schizophrenia. Dysfunction of subventricular neural stem cells (NSC), located partially overlapping Acc is the cause of D-neuron decrease in Acc. DA hyperactivity, which inhibits NSC proliferation, causes disease progression of schizophrenia. The highlight is the rational that the “D-cell hypothesis (TA hypothesis) of schizophrenia” is a pivotal theory to link NSC dysfunction hypothesis to DA hypothesis. From a therapeutic direction, (1) TAAR1 agonists, (2) DA D2 antagonists, and (3) neurotrophic substances have potential to normalize mesolimbic DA hyperactivity. To develop novel therapeutic strategies, metabolisms of TAAR1 ligands, and NSC- and D-neuron-pathophysiology of neuropsychiatric illnesses should further be explored.

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Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00178.2015 ◽

2015 ◽

Vol 309 (1) ◽

pp. H103-H113 ◽

Cited By ~ 8

Author(s):

Jungsil Kim ◽

Jesse D. Procknow ◽

Hiromi Yanagisawa ◽

Jessica E. Wagenseil

Keyword(s):

Gene Expression ◽

Matrix Protein ◽

Mechanical Response ◽

Aortic Aneurysms ◽

Extracellular Matrix Protein ◽

Elastic Fibers ◽

Newborn Mice ◽

Thoracic Aortic Aneurysms ◽

Neutrophil Collagenase

Fibulin-4 is an extracellular matrix protein that is essential for proper assembly of arterial elastic fibers. Mutations in fibulin-4 cause cutis laxa with thoracic aortic aneurysms (TAAs). Sixty percent of TAAs occur in the ascending aorta (AA). Newborn mice lacking fibulin-4 ( Fbln4−/−) have aneurysms in the AA, but narrowing in the descending aorta (DA), and are a unique model to investigate locational differences in aneurysm susceptibility. We measured mechanical behavior and gene expression of AA and DA segments in newborn Fbln4−/− and Fbln4+/+ mice. Fbln4−/− AA has increased diameters compared with Fbln4+/+ AA and Fbln4−/− DA at most applied pressures, confirming genotypic and locational specificity of the aneurysm phenotype. When diameter compliance and tangent modulus were calculated from the mechanical data, we found few significant differences between genotypes, suggesting that the mechanical response to incremental diameter changes is similar, despite the fragmented elastic fibers in Fbln4−/− aortas. Fbln4−/− aortas showed a trend toward increased circumferential stretch, which may be transmitted to smooth muscle cells (SMCs) in the wall. Gene expression data suggest activation of pathways for SMC proliferation and inflammation in Fbln4−/− aortas compared with Fbln4+/+. Additional genes in both pathways, as well as matrix metalloprotease-8 ( Mmp8), are upregulated specifically in Fbln4−/− AA compared with Fbln4+/+ AA and Fbln4−/− DA. Mmp8 is a neutrophil collagenase that targets type 1 collagen, and upregulation may be necessary to allow diameter expansion in Fbln4−/− AA. Our results provide molecular and mechanical targets for further investigation in aneurysm pathogenesis.

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Content and turnover of extracellular matrix protein in human “Non-specific” and inflammatory abdominal aortic aneurysms

European Journal of Vascular Surgery ◽

10.1016/s0950-821x(05)80368-8 ◽

1993 ◽

Vol 7 (5) ◽

pp. 546-553 ◽

Cited By ~ 17

Author(s):

Mauro Gargiulo ◽

Andrea Stella ◽

Michele Spina ◽

Gianluca Faggioli ◽

Giovanna Cenacchi ◽

...

Keyword(s):

Extracellular Matrix ◽

Matrix Protein ◽

Abdominal Aortic Aneurysms ◽

Aortic Aneurysms ◽

Extracellular Matrix Protein ◽

Abdominal Aortic

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Interaction between cartilage oligomeric matrix protein and extracellular matrix protein 1 mediates endochondral bone growth

Matrix Biology ◽

10.1016/j.matbio.2010.01.007 ◽

2010 ◽

Vol 29 (4) ◽

pp. 276-286 ◽

Cited By ~ 27

Author(s):

Li Kong ◽

Qingyun Tian ◽

Fengjin Guo ◽

Maria T. Mucignat ◽

Roberto Perris ◽

...

Keyword(s):

Extracellular Matrix ◽

Cartilage Oligomeric Matrix Protein ◽

Matrix Protein ◽

Bone Growth ◽

Extracellular Matrix Protein ◽

Endochondral Bone ◽

Extracellular Matrix Protein 1

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A Novel Gene, CBP1, Encoding a Putative Extracellular Chitin-Binding Protein, May Play an Important Role in the Hydrophobic Surface Sensing of Magnaporthe grisea During Appressorium Differentiation

Molecular Plant-Microbe Interactions ◽

10.1094/mpmi.2002.15.5.437 ◽

2002 ◽

Vol 15 (5) ◽

pp. 437-444 ◽

Cited By ~ 62

Author(s):

Takashi Kamakura ◽

Syuichi Yamaguchi ◽

Ken-ichiro Saitoh ◽

Tohru Teraoka ◽

Isamu Yamaguchi

Keyword(s):

Germ Tube ◽

Matrix Protein ◽

Magnaporthe Grisea ◽

Binding Protein ◽

Consensus Sequence ◽

Extracellular Matrix Protein ◽

Specific Gene ◽

Physical Factors ◽

Binding Motif ◽

Chitin Binding Protein

The conidial germ tube of the rice blast fungus, Magnaporthe grisea, differentiates a specialized cell, an appressorium, required for penetration into the host plant. Formation of the appressorium is also observed on artificial solid substrata such as polycarbonate. A novel emerging germ tube-specific gene, CBP1 (chitin-binding protein), was found in a cDNA subtractive differential library. CBP1 coded for a putative extracellular protein (signal peptide) with two similar chitin-binding domains at both ends of a central domain with homology to fungal chitin deacetylases and with a C-terminus domain rich in Ser/Thr related extracellular matrix protein such as agglutinin. The consensus sequence of the chitin-binding domain found in CBP1 has never been reported in fungi and is similar to the chitin-binding motif in plant lectins and plant chitinases classes I and IV. CBP1 was disrupted in order to identify its function. Null mutants of CBP1 failed to differentiate appressoria normally on artificial surface but succeeded in normally differentiating appressoria on the plant leaf surface. Since the null mutant Cbp1- showed abnormal appressorium differentiation only on artificial surfaces and was sensitive to the chemical inducers, CBP1 seemed to play an important role in the recognition of physical factors on solid surfaces.

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