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  • 1
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    Identification of Adipsin as a Novel Prognostic Biomarker in Patients With Coronary Artery Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Journal of the American Heart Association Vol. 8, No. 23 ( 2019-12-03)
    Details
    In: Journal of the American Heart Association, Ovid Technologies (Wolters Kluwer Health), Vol. 8, No. 23 ( 2019-12-03)
    Abstract: Circulating proteins are exposed to vascular endothelial layer and influence their functions. Among them, adipsin is a member of the trypsin family of peptidases and is mainly secreted from adipocytes, monocytes, and macrophages, catalyzing the rate‐limiting step of the alternative complement pathway. However, its pathophysiological role in cardiovascular disease remains to be elucidated. Here, we examined whether serum adipsin levels have a prognostic impact in patients with coronary artery disease. Methods and Results In 370 consecutive patients undergoing diagnostic coronary angiography, we performed a cytokine array analysis for screening serum levels of 50 cytokines/chemokines and growth factors. Among them, classification and regression analysis identified adipsin as the best biomarker for prediction of their long‐term prognosis (median 71 months; interquartile range, 55–81 months). Kaplan–Meier curve showed that higher adipsin levels (≥400 ng/ mL ) were significantly associated with all‐cause death (hazard ratio [HR], 4.2; 95% CI, 1.7–10.6 [ P 〈 0.001]) and rehospitalization ( HR , 2.4; 95% CI, 1.7–3.5 [ P 〈 0.001]). Interestingly, higher high‐sensitivity C‐reactive protein levels (≥1 mg/L) were significantly correlated with all‐cause death ( HR, 3.2; 95% CI, 1.7–5.9 [ P 〈 0.001]) and rehospitalization ( HR, 1.5, 95% CI, 1.1–1.9 [ P 〈 0.01]). Importantly, the combination of adipsin (≥400 ng/ mL ) and high‐sensitivity C‐reactive protein (≥1 mg/L) was more significantly associated with all‐cause death ( HR, 21.0; 95% CI, 2.9–154.1 [ P 〈 0.001]). Finally, the receiver operating characteristic curve demonstrated that serum adipsin levels predict the death caused by acute myocardial infarction in patients with coronary artery disease (C‐statistic, 0.847). Conclusions These results indicate that adipsin is a novel biomarker that predicts all‐cause death and rehospitalization in patients with coronary artery disease, demonstrating the novel aspects of the alternative complementary system in the pathogenesis of coronary artery disease.
    Type of Medium: Online Resource
    ISSN: 2047-9980
    URL: Article
    DOI: 10.1161/JAHA.119.013716
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
    detail.hit.zdb_id: 2653953-6
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  • 2
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    Crucial Role of ROCK1 to Maintain Contractile Function in Response to Chronic Pressure-Overload in Mice
    Elsevier BV ; 2016
    In:  Journal of Cardiac Failure Vol. 22, No. 9 ( 2016-09), p. S207-
    Details
    In: Journal of Cardiac Failure, Elsevier BV, Vol. 22, No. 9 ( 2016-09), p. S207-
    Type of Medium: Online Resource
    ISSN: 1071-9164
    URL: Article
    DOI: 10.1016/j.cardfail.2016.07.289
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2016
    detail.hit.zdb_id: 2048826-9
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  • 3
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    Abstract 507: Plasma Cyclophilin A as a Useful Biomarker for Effective Percutaneous Transluminal Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Hypertension
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. suppl_1 ( 2015-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. suppl_1 ( 2015-05)
    Abstract: Background: Cyclophilin A (CyPA, encoded by Ppia) is secreted from pulmonary vascular smooth muscle cells in response to several stimuli including mechanical stretch and hypoxia. Recently, we demonstrated that extracellular CyPA and vascular Basigin (Bsg, encoded by Bsg) are crucial for hypoxia-induced PH by inducing growth factor secretion, inflammatory cell recruitment and VSMC proliferation in mice. Moreover, we demonstrated that high plasma CyPA levels are significantly associated with poor outcome (death or lung transplantation) in patients with pulmonary arterial hypertension (PAH). In this study, we examined plasma levels of CyPA in patients with chronic thromboembolic pulmonary hypertension (CTEPH) before and after percutaneous transluminal pulmonary angioplasty (PTPA), which is recently developed as a catheter-based therapy. Methods and Results: In consecutive 86 PTPA sessions in 24 patients, we examined the relationship between plasma CyPA levels, the severity of CTEPH and hemodynamic improvements after PTPA. We measured plasma CyPA levels by an immunoassay based on the sandwich technique. Plasma CyPA levels (ng/mL) were significantly elevated in patients with CTEPH (13.8±6.0, n=24) compared with those without PH (4.9±4.0, n=7) or healthy controls (4.6±2.8, n=18) (both P 〈 0.001). Moreover, the severity of CTEPH assessed by pulmonary vascular resistance (PVR) correlated with plasma levels of CyPA, IFN-α2, stem cell factor and adipsin (all P 〈 0.05). PTPA significantly reduced mean pulmonary artery pressure (P 〈 0.05), PVR (P 〈 0.01) and improved long-term prognosis compared with historical controls. Importantly, PTPA significantly reduced plasma CyPA levels in patients with CTEPH (5.4±4.1, P 〈 0.001), suggesting that plasma CyPA is useful for evaluation of therapeutic effects of PTPA. Finally, we observed significant increase in anti-inflammatory cytokines (interleukin-4, 7, 13) and reduction in stem cell growth factor-β and adipsin (all P 〈 0.05) after PTPA, suggesting improved metabolic and inflammatory state in CTEPH patients. Conclusions: These results indicate that plasma levels of CyPA are significantly increased in CTEPH patients and could be considered as an effective biomarker for assessment of the effects of PTPA.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.35.suppl_1.507
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
    detail.hit.zdb_id: 1494427-3
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  • 4
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    Prognostic Impacts of Plasma Levels of Cyclophilin A in Patients With Coronary Artery Disease
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 37, No. 4 ( 2017-04), p. 685-693
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 37, No. 4 ( 2017-04), p. 685-693
    Abstract: Cyclophilin A (CyPA) is secreted from vascular smooth muscle cells, inflammatory cells, and activated platelets in response to oxidative stress. We have recently demonstrated that plasma CyPA level is a novel biomarker for diagnosing coronary artery disease. However, it remains to be elucidated whether plasma CyPA levels also have a prognostic impact in such patients. Approach and Results— In 511 consecutive patients undergoing diagnostic coronary angiography, we measured the plasma levels of CyPA, high-sensitivity C-reactive protein (hsCRP), and brain natriuretic peptide and evaluated their prognostic impacts during the follow-up (42 months, interquartile range: 25–55 months). Higher CyPA levels (≥12 ng/mL) were significantly associated with all-cause death, rehospitalization, and coronary revascularization. Higher hsCRP levels (≥1 mg/L) were also significantly correlated with the primary end point and all-cause death, but not with rehospitalization or coronary revascularization. Similarly, higher brain natriuretic peptide levels (≥100 pg/mL) were significantly associated with all-cause death and rehospitalization, but not with coronary revascularization. Importantly, the combination of CyPA (≥12 ng/mL) and hsCRP (≥1 mg/L) was more significantly associated with all-cause death (hazard ratio, 21.2; 95% confidence interval, 4.9–92.3,; P 〈 0.001) than CyPA (≥12 ng/mL) or hsCRP (≥1 mg/L) alone. Conclusions— The results indicate that plasma CyPA levels can be used to predict all-cause death, rehospitalization, and coronary revascularization in patients with coronary artery disease and that when combined with other biomarkers (hsCRP and brain natriuretic peptide levels), the CyPA levels have further enhanced prognostic impacts in those patients.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.116.308986
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
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  • 5
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    Small GTP-Binding Protein GDP Dissociation Stimulator Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Vol. 138, No. 21 ( 2018-11-20), p. 2413-2433
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 138, No. 21 ( 2018-11-20), p. 2413-2433
    Abstract: Thoracic aortic aneurysm (TAA) and dissection are fatal diseases that cause aortic rupture and sudden death. The small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Previous studies revealed that reduced force generation in aortic smooth muscle cells (AoSMCs) causes TAA and thoracic aortic dissection. Methods: To examine the role of SmgGDS in TAA formation, we used an angiotensin II (1000 ng·min −1 ·kg −1 , 4 weeks)–induced TAA model. Results: We found that 33% of Apoe −/− SmgGDS +/− mice died suddenly as a result of TAA rupture, whereas there was no TAA rupture in Apoe −/− control mice. In contrast, there was no significant difference in the ratio of abdominal aortic aneurysm rupture between the 2 genotypes. We performed ultrasound imaging every week to follow up the serial changes in aortic diameters. The diameter of the ascending aorta progressively increased in Apoe −/− SmgGDS +/− mice compared with Apoe −/− mice, whereas that of the abdominal aorta remained comparable between the 2 genotypes. Histological analysis of Apoe −/− SmgGDS +/− mice showed dissections of major thoracic aorta in the early phase of angiotensin II infusion (day 3 to 5) and more severe elastin degradation compared with Apoe −/− mice. Mechanistically, Apoe −/− SmgGDS +/− mice showed significantly higher levels of oxidative stress, matrix metalloproteinases, and inflammatory cell migration in the ascending aorta compared with Apoe −/− mice. For mechanistic analyses, we primary cultured AoSMCs from the 2 genotypes. After angiotensin II (100 nmol/L) treatment for 24 hours, Apoe −/− SmgGDS +/− AoSMCs showed significantly increased matrix metalloproteinase activity and oxidative stress levels compared with Apoe −/− AoSMCs. In addition, SmgGDS deficiency increased cytokines/chemokines and growth factors in AoSMCs. Moreover, expressions of fibrillin-1 ( FBN1 ), α-smooth muscle actin ( ACTA2 ), myosin-11 ( MYH11 ), MYLLK , and PRKG1 , which are force generation genes, were significantly reduced in Apoe −/− SmgGDS +/− AoSMCs compared with Apoe −/− AoSMCs. A similar tendency was noted in AoSMCs from patients with TAA compared with those from control subjects. Finally, local delivery of the SmgGDS gene construct reversed the dilation of the ascending aorta in Apoe −/− SmgGDS +/− mice. Conclusions: These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.118.035648
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1466401-X
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  • 6
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    Online Resource
    Abstract 315: SmgGDS Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 38, No. Suppl_1 ( 2018-05)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 38, No. Suppl_1 ( 2018-05)
    Abstract: Background: Thoracic aortic aneurysm (TAA) and dissection (TAD) are fatal diseases, which cause aortic rupture and sudden death. The small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Previous studies revealed that reduced force generation in AoSMCs causes TAA and TAD. Methods and Results: To examine the role of SmgGDS in TAA formation, we employed an angiotensin II (AngII, 1,000 ng/min/kg, 4weeks)-induced TAA model in Apoe -/- SmgGDS +/- mice, in which 33% died suddenly due to TAA rupture, whereas there was no TAA rupture in Apoe -/- control mice. In contrast, there was no significant difference in the ratio of AAA rupture between the two genotypes. We performed ultrasound imaging every week to follow the serial changes in aortic diameters. The diameter of the ascending aorta progressively increased in Apoe -/- SmgGDS +/- mice compared with Apoe -/- mice, whereas that of the abdominal aorta remained comparable between the two genotypes. Histological analysis of Apoe -/- SmgGDS +/- mice showed dissections of major thoracic aorta in the early phase of AngII infusion (day 3~5) and more severe elastin degradation compared with Apoe -/- mice. Mechanistically, Apoe -/- SmgGDS +/- mice showed significantly higher levels of oxidative stress, matrix metalloproteinases, and inflammatory cell migration in the ascending aorta compared with Apoe -/- mice. For mechanistic analyses, we primary cultured AoSMCs from the 2 genotypes. After AngII (100 nM) treatment for 24 hours, Apoe -/- SmgGDS +/- AoSMCs showed significantly increased MMP activity and oxidative stress levels compared with Apoe -/- AoSMCs. In addition, SmgGDS deficiency increased cytokines/chemokines and growth factors in AoSMCs. Moreover, expressions of FBN1 , ACTA2 , MYH11 , MLK and PRKG1 , which are force generation genes, were significantly reduced in Apoe -/- SmgGDS +/- AoSMCs compared with Apoe -/- AoSMCs. Similar tendency was noted in AoSMCs from TAA patients compared with those from controls. Finally, local delivery of the SmgGDS gene construct reversed the dilation of the ascending aorta in Apoe -/- SmgGDS +/- mice. Conclusions: These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/atvb.38.suppl_1.315
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 1494427-3
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  • 7
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    Online Resource
    Identification of Emetine as a Therapeutic Agent for Pulmonary Arterial Hypertension : Novel Effects of an Old Drug
    Ovid Technologies (Wolters Kluwer Health) ; 2019
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 39, No. 11 ( 2019-11), p. 2367-2385
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 39, No. 11 ( 2019-11), p. 2367-2385
    Abstract: Excessive proliferation and apoptosis resistance are special characteristics of pulmonary artery smooth muscle cells (PASMCs) in pulmonary arterial hypertension (PAH). However, the drugs in clinical use for PAH target vascular dilatation, which do not exert adequate effects in patients with advanced PAH. Here, we report a novel therapeutic effect of emetine, a principal alkaloid extracted from the root of ipecac clinically used as an emetic and antiprotozoal drug. Approach and Results: We performed stepwise screenings for 5562 compounds from original library. First, we performed high-throughput screening with PASMCs from patients with PAH (PAH-PASMCs) and found 80 compounds that effectively inhibited proliferation. Second, we performed the repeatability and counter assay. Finally, we performed a concentration-dependent assay and found that emetine inhibits PAH-PASMC proliferation. Interestingly, emetine significantly reduced protein levels of HIFs (hypoxia-inducible factors; HIF-1α and HIF-2α) and downstream PDK1 (pyruvate dehydrogenase kinase 1). Moreover, emetine significantly reduced the protein levels of RhoA (Ras homolog gene family, member A), Rho-kinases (ROCK1 and ROCK2 [rho-associated coiled-coil containing protein kinases 1 and 2]), and their downstream CyPA (cyclophilin A), and Bsg (basigin) in PAH-PASMCs. Consistently, emetine treatment significantly reduced the secretion of cytokines/chemokines and growth factors from PAH-PASMCs. Interestingly, emetine reduced protein levels of BRD4 (bromodomain-containing protein 4) and downstream survivin, both of which are involved in many cellular functions, such as cell cycle, apoptosis, and inflammation. Finally, emetine treatment ameliorated pulmonary hypertension in 2 experimental rat models, accompanied by reduced inflammatory changes in the lungs and recovered right ventricular functions. Conclusions: Emetine is an old but novel drug for PAH that reduces excessive proliferation of PAH-PASMCs and improves right ventricular functions.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.119.313309
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2019
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  • 8
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    Identification of Celastrol as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension and Right Ventricular Failure Through Suppression of Bsg (Basigin)/CyPA (Cyclophilin A)
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 41, No. 3 ( 2021-03), p. 1205-1217
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 41, No. 3 ( 2021-03), p. 1205-1217
    Abstract: Pulmonary arterial hypertension is characterized by abnormal proliferation of pulmonary artery smooth muscle cells and vascular remodeling, which leads to right ventricular (RV) failure. Bsg (Basigin) is a transmembrane glycoprotein that promotes myofibroblast differentiation, cell proliferation, and matrix metalloproteinase activation. CyPA (cyclophilin A) binds to its receptor Bsg and promotes pulmonary artery smooth muscle cell proliferation and inflammatory cell recruitment. We previously reported that Bsg promotes cardiac fibrosis and failure in the left ventricle in response to pressure-overload in mice. However, the roles of Bsg and CyPA in RV failure remain to be elucidated. Approach and Results: First, we found that protein levels of Bsg and CyPA were upregulated in the heart of hypoxia-induced pulmonary hypertension (PH) in mice and monocrotaline-induced PH in rats. Furthermore, cardiomyocyte-specific Bsg-overexpressing mice showed exacerbated RV hypertrophy, fibrosis, and dysfunction compared with their littermates under chronic hypoxia and pulmonary artery banding. Treatment with celastrol, which we identified as a suppressor of Bsg and CyPA by drug screening, decreased proliferation, reactive oxygen species, and inflammatory cytokines in pulmonary artery smooth muscle cells. Furthermore, celastrol treatment ameliorated RV systolic pressure, hypertrophy, fibrosis, and dysfunction in hypoxia-induced PH in mice and SU5416/hypoxia-induced PH in rats with reduced Bsg, CyPA, and inflammatory cytokines in the hearts and lungs. Conclusions: These results indicate that elevated Bsg in pressure-overloaded RV exacerbates RV dysfunction and that celastrol ameliorates RV dysfunction in PH model animals by suppressing Bsg and its ligand CyPA. Thus, celastrol can be a novel drug for PH and RV failure that targets Bsg and CyPA. Graphic Abstract: A graphic abstract is available for this article.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.120.315731
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
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  • 9
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    Rho-Kinase Inhibition During Early Cardiac Development Causes Arrhythmogenic Right Ventricular Cardiomyopathy in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 35, No. 10 ( 2015-10), p. 2172-2184
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 35, No. 10 ( 2015-10), p. 2172-2184
    Abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by fibrofatty changes of the right ventricle, ventricular arrhythmias, and sudden death. Though ARVC is currently regarded as a disease of the desmosome, desmosomal gene mutations have been identified only in half of ARVC patients, suggesting the involvement of other associated mechanisms. Rho-kinase signaling is involved in the regulation of intracellular transport and organizes cytoskeletal filaments, which supports desmosomal protein complex at the myocardial cell–cell junctions. Here, we explored whether inhibition of Rho-kinase signaling is involved in the pathogenesis of ARVC. Approach and Results— Using 2 novel mouse models with SM22α- or αMHC-restricted overexpression of dominant-negative Rho-kinase, we show that mice with Rho-kinase inhibition in the developing heart (SM22α-restricted) spontaneously develop cardiac dilatation and dysfunction, myocardial fibrofatty changes, and ventricular arrhythmias, resulting in premature sudden death, phenotypes fulfilling the criteria of ARVC in humans. Rho-kinase inhibition in the developing heart results in the development of ARVC phenotypes in dominant-negative Rho-kinase mice through 3 mechanisms: (1) reduction of cardiac cell proliferation and ventricular wall thickness, (2) stimulation of the expression of the proadipogenic noncanonical Wnt ligand, Wnt5b, and the major adipogenic transcription factor, PPARγ (peroxisome proliferator activated receptor-γ), and inhibition of Wnt/β-catenin signaling, and (3) development of desmosomal abnormalities. These mechanisms lead to the development of cardiac dilatation and dysfunction, myocardial fibrofatty changes, and ventricular arrhythmias, ultimately resulting in sudden premature death in this ARVC mouse model. Conclusions— This study demonstrates a novel crucial role of Rho-kinase inhibition during cardiac development in the pathogenesis of ARVC in mice.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.115.305872
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 10
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    Basigin Promotes Cardiac Fibrosis and Failure in Response to Chronic Pressure Overload in Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 36, No. 4 ( 2016-04), p. 636-646
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 36, No. 4 ( 2016-04), p. 636-646
    Abstract: Basigin (Bsg) is a transmembrane glycoprotein that activates matrix metalloproteinases and promotes inflammation. However, the role of Bsg in the pathogenesis of cardiac hypertrophy and failure remains to be elucidated. We examined the role of Bsg in cardiac hypertrophy and failure in mice and humans. Approach and Results— We performed transverse aortic constriction in Bsg +/– and in wild-type mice. Bsg +/– mice showed significantly less heart and lung weight and cardiac interstitial fibrosis compared with littermate controls after transverse aortic constriction. Both matrix metalloproteinase activities and oxidative stress in loaded left ventricle were significantly less in Bsg +/– mice compared with controls. Echocardiography showed that Bsg +/– mice showed less hypertrophy, less left ventricular dilatation, and preserved left ventricular fractional shortening compared with littermate controls after transverse aortic constriction. Consistently, Bsg +/– mice showed a significantly improved long-term survival after transverse aortic constriction compared with Bsg +/+ mice, regardless of the source of bone marrow ( Bsg +/+ or Bsg +/– ). Conversely, cardiac-specific Bsg-overexpressing mice showed significantly poor survival compared with littermate controls. Next, we isolated cardiac fibroblasts and examined their responses to angiotensin II or mechanical stretch. Both stimuli significantly increased Bsg expression, cytokines/chemokines secretion, and extracellular signal–regulated kinase/Akt/JNK activities in Bsg +/+ cardiac fibroblasts, all of which were significantly less in Bsg +/– cardiac fibroblasts. Consistently, extracellular and intracellular Bsg significantly promoted cardiac fibroblast proliferation. Finally, serum levels of Bsg were significantly elevated in patients with heart failure and predicted poor prognosis. Conclusions— These results indicate the crucial roles of intracellular and extracellular Bsg in the pathogenesis of cardiac hypertrophy, fibrosis, and failure in mice and humans.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.115.306686
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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