Loss of smooth muscle SDF-1/CXCL12 leads to cardiac hypertrophy and aortic valve stenosis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S.K Ghadge ◽  
M Messner ◽  
H Seiringer ◽  
T Zeller ◽  
D Boernigen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Stenosis ◽  
Cardiac Hypertrophy ◽  
Smooth Muscle Cells ◽  
Aortic Valve Stenosis ◽  
Cardiac Fibrosis ◽  
Muscle Cells ◽  
Funding Source ◽  
Lineage Tracking

Abstract Background Stromal cell-derived factor-1 (SDF-1 or CXCL12) and its receptors CXCR4/CXCR7 have prominent role in cardiovascular development and myocardial repair following ischemic injury. Nevertheless, detailed mechanisms of the cell specific role of SDF-1 are poorly understood. Since SDF-1-EGFP lineage tracking revealed high expression of SDF-1 in smooth muscle cells, we aimed to investigate the cell specific role by generating a smooth muscle cell specific SDF-1 (SM-SDF-1−/−) knockout mouse model. Methods SDF-1 expression was analyzed utilizing SDF-1-EGFP reporter mice. Conditional SM-SDF-1 KO mice were generated using Tagln-Cre; SDF-1fl/fl mice. Hearts were analysed with histology and high-resolution episcopic microscopy. Cardiac function was assessed utilizing echocardiography. RNAseq, qRT-PCR, flow cytometry and western blotting were performed. Cardiac fibrosis, apoptotic index, cell proliferation, aortic valve calcification were analyzed. SM-SDF-1−/− mice were treated with the CXCR7 agonist TC14012 (10mg/kg/I.P). Results SDF-1-EGFP lineage tracking and immunofluorescence revealed high expression of SDF-1 particularly in smooth muscle cells and less frequently in perivascular and endothelial cells. Conditional SM-SDF-1−/− mice showed a high pre- and perinatal mortality (50%). Immunohistochemistry of SM-SDF-1−/− mice revealed severe cardiac hypertrophy, associated with increased cardiac fibrosis, apoptotic cell death, thinned and dilated arteries and significantly decreased M2 like CD11b+/CD206+ cells. Echocardiography confirmed concentric hypertrophy, with decreased stroke volume. As a possible reason for cardiac hypertrophy, SDF-1 mutants exhibited aortic stenosis due to aortic valve thickening associated with downregulation of the SDF-1 co-receptor CXCR7. We further noticed increased plasma levels of SDF-1 in aortic stenosis patients suggesting a cardioprotective role. Transcriptome analyses from KO hearts showed an abnormal extracellular matrix (ECM) remodelling with a specific upregulation of the important valve related proteoglycans Versican, Glycan. Western blot analysis revealed activation of AKT and ERK, whereas CXCR7 expression was significantly downregulated in KO mice. To rescue the phenotype we treated KO mice with the CXCR7 agonist (TC14012) which partially attenuated aortic valve remodelling through activation of the ERK signalling pathway. Conclusion Our data suggest that SDF-1 is critically involved in maintaining the homeostasis of the aortic valve by regulating CXCR7 signalling. Pharmacological activation of CXCR7 might be a promising therapeutic target to limit the progression of aortic valve stenosis. Ghadge_SM-SDF-1−/− Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Austrian Science Fund, Austrian research promotion agency

6090Conditional ablation of SDF-1/CXCL12 in smooth muscle cells leads to severe cardiac hypertrophy and aortic valve stenosis

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Messner ◽  
S K Ghadge ◽  
H Seiringer ◽  
T Zeller ◽  
D Boernigen ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Stenosis ◽  
Cardiac Hypertrophy ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Muscle Cells ◽  
Cardiovascular Development ◽  
Lineage Tracking

Abstract Background Stromal cell derived factor-1 (SDF-1) and its corresponding receptors CXCR4 & CXCR7 have been shown to play pivotal roles during cardiovascular development, cardiac repair and tissue homeostasis after ischemia. Stabilization of the SDF-1/CXCR4+ axis has been shown to provide beneficial effects on myocardial repair. Nevertheless, detailed mechanisms of the cell specific role of SDF-1 are poorly understood. Since SDF-1-EGFP lineage tracking revealed high expression of SDF-1 in smooth muscle cells, we aimed to investigate the cell specific role by generating a smooth muscle cell specific SDF-1 (SM-SDF-1 KO) knockout mouse model. Methods SDF-1 expression was analyzed utilizing SDF-1-EGFP reporter mice. SM-SDF-1 KO mice were generated using Cre/LoxP technology (SM22a-Cre; SDF-1fl/fl). Morphology was analysed with immunohistochemistry and immunofluorescence. Cardiac function was assessed utilizing echocardiography and millar tip catheterization. Whole transcriptome analysis, qRT-PCR and western blotting were performed. Further, apoptotic index and cell proliferation were quantified by TUNEL assay and PH3 immunostaining, respectively. Results SDF-1-EGFP lineage tracking and immunofluorescence analysis revealed high expression of SDF-1 particularly in smooth muscle cells and less frequently in perivascular and endothelial cells. Conditional SM-SDF-1 KO mice showed a high pre- and perinatal mortality (50%). Immunohistochemistry in surviving adult SM-SDF-1 KO mice revealed a severe cardiac hypertrophy phenotype, associated with increased cardiac fibrosis and apoptotic cell death. SM-SDF-1 KO mice revealed very thin and dilated arteries. Echocardiography measurements confimed concentric hypertrophy, and decreased stroke volume reflecting restrictive hypertrophic cardiomyopathy. Immunohistochemistry confirmed pronounced hypertrophy of cardiomyocytes. Additionally, we found evidence for enhanced proliferation markers in cardiomyocytes of SM-SDF-1 KO mice. Transcriptome analyses from KO hearts vs. non-ablated littermates identified over 150 significantly up- and downregulated genes. Western blot analysis for HIF-1α, AKT and ERK cell-signalling pathways were significantly elevated, whereas Rho Kinase signalling was specifically downregulated in SM-SDF-1 KO mice. As a possible reason for the hypertrophic phenotype, SDF-1 mutants exhibited aortic stenosis due to aortic valve thickening associated with upregulation of the extracellular proteoglycan versican anddownregulation of the SDF-1 co-receptor CXCR7. We further noticed increased plasma levels of SDF-1 in aortic stenosis patients suggesting a cardioprotective role. Conclusion Our data suggest that smooth muscle cell specific expression of SDF-1 plays a prominent role in cardiovascular development leadingto cardiac hypertrophy in adult animals. Our data further suggest that SDF-1 is involved in maintaining the homeostasis of the aortic valve, possibly by regulating versican. Acknowledgement/Funding FWF Austria

Smooth muscle cell-specific SOCS3 deficiency promote pericardial fibrosis and diastolic dysfunction in aging mice

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Yanai ◽  
H Yasukawa ◽  
K Mawatari ◽  
T Sasaki ◽  
J Takahashi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Diastolic Dysfunction ◽  
Interstitial Fibrosis ◽  
Muscle Cells ◽  
Left Ventricular ◽  
Funding Source ◽  
Wild Type

Abstract Background Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible negative regulator of signal transducer and activator of transcription-3 (STAT3) signaling pathway. We have previously shown that cardiac-specific SOCS3 deficiency spontaneously develop cardiac dysfunction with advanced age. However, the role of SOCS3 in smooth muscle cells in cardiovascular pathophysiology remains elusive. In this study, we determined whether STAT3 and SOCS3 in smooth muscle cells would play a role in cardiovascular pathophysiology. Methods and results To target inactivation of the SOCS3 gene to smooth muscle cells, SOCS3-flox mice were bred with transgenic mice expressing Cre recombinase under control of the mouse SM22-α promoter (sm-SOCS3-KO mice). Left ventricular weight to body weight ratio was significantly increased in sm-SOCS3-KO mice compared with wild-type mice at 12 months of age (p<0.05). Echocardiographic analyses of smSOCS3-KO mice showed significantly increased left ventricular diastolic dysfunction compared with wild-type from 12 months of age (p<0.05). Sirius-red staining revealed that thickness of pericardium and cardiac interstitial fibrosis in sm-SOCS3-KO mice were markedly greater compared with wild-type mice at 12 months of age (p<0.05). Western blot analyses showed that phosphorylated STAT3 was significantly increased in sm-SOCS3-KO hearts compared with wild-type mice at 12 months of age (p<0.05), whereas no significant differences were observed at 2 months of age. To investigate the mechanism that gave rise to promoted cardiac fibrosis and diastolic dysfunction during aging in sm-SOCS3-KO, we conducted a real-time PCR array analysis for fibrosis. The expression of pro-fibrotic CTGF (connective tissue growth factor), PDGFb (platelet growth factor-b), and TGF (transforming growth factor) family genes including TGFb1, TGFb2, and TGFb3, were significantly higher in sm-SOCS3-KO hearts than those in wild-type at 6 months of age. Conclusion Thus, smooth muscle cell-specific SOCS3 deletion induces increased pericardial fibrosis, cardiac interstitial fibrosis, and increased diastolic dysfunction in aging mice, possibly through the augmentation of pro-fibrotic growth factors. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Grant JSPS KAKENHI

Smooth muscle cells in the cusps of the aortic valve of pigs

1978 ◽  
Vol 34 (12) ◽  
pp. 1636-1638 ◽  
Author(s):  
A. Bairati ◽  
S. De Biasi ◽  
F. Pilotto
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Smooth Muscle Cells ◽  
Muscle Cells

Abstract 397: Analysis of Cell Phenotype in Relation to TGFβ Treatment of Aortic Smooth Muscle Cells and Myofibroblasts Isolated from Aortas and Valves of Thoracic Aortic Aneurysm Patients with a Tricuspid or a Bicuspid Valve

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Valentina Paloschi ◽  
Lasse Folkersen ◽  
Sanela Kurtovic ◽  
Dick Wagsater ◽  
Anders Franco Cereceda ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Aortic Aneurysm ◽  
Smooth Muscle Cells ◽  
Thoracic Aortic Aneurysm ◽  
Muscle Cells ◽  
Cell Types ◽  
Cell Phenotype ◽  
Matrix Remodeling ◽  
Exon Arrays

Background Thoracic aortic aneurysm (TAA) is a pathological widening of the aorta, due to degeneration of extracellular matrix (ECM) and loss of smooth muscle cells (SMCs). Bicuspid aortic valve (BAV) is a congenital disorder present in 1-2 % of the population which makes TAA associated with BAV a common complication. Previously we showed that aortas isolated from BAV and normal tricuspid aortic valve (TAV) patients are different both at gene and protein levels. Particularly, differences in the TGFβ pathway seem to be crucial players in aneurysm development, affecting matrix remodeling and wound healing. Since SMCs and myofibroblasts are the critical cells responsible for these activities, we evaluated different properties of the cells focusing on fibronectin (FN) and its spliced versions, a target gene of TGFβ. Interestingly, extra domain A of FN (EDA) was previously described for its roles in vascular morphogenesis, as well as in processes like migration and proliferation. Methods and results Biopsies from the thoracic aorta and Aortic valves were collected during Elective Aortic Valve Replacement Surgery. mRNA expression was analyzed in the ascending aorta by Affymetrix Exon arrays in patients with TAV (n=46) and BAV (n=77). Expression of EDA was found increased only in dilated aortas from TAV patients but not in BAV patients. Primary SMCs were isolated with the explant outgrowth technique from aortas of BAV and TAV patients (n=15). Myofibroblasts were isolated by collagenase digestion from BAV and TAV valves (n=30). Cells were cultured and treated with TGFβ at a concentration of 20 ng/ml for 6h. TGFβ treatment influenced the splicing of FN and enhanced the formation of EDA-containing FN in SMCs from TAV patients but not in cells derived from BAV patients. We have not observed clear differences in SMC proliferation and migration. Myofibrolasts analysis is ongoing. Conclusions So far, our results suggest that despite a decreased EDA-fibronectin expression in BAV cells, the phenotype of SMCs isolated from BAV and TAV patients in culture does not differ. However, impaired TGFβ signaling that may result in the increased susceptibility of BAV patients to develop TAA could be due to effects on other cell types.

scholarly journals Phenotypic and Functional Changes of Endothelial and Smooth Muscle Cells in Thoracic Aortic Aneurysms

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Anna Malashicheva ◽  
Daria Kostina ◽  
Aleksandra Kostina ◽  
Olga Irtyuga ◽  
Irina Voronkina ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Aortic Valve ◽  
Smooth Muscle Cells ◽  
Aortic Wall ◽  
Muscle Cells ◽  
Aortic Aneurysms ◽  
Cell Phenotype ◽  
Functional Markers ◽  
Thoracic Aortic Aneurysms

Thoracic aortic aneurysm develops as a result of complex series of events that alter the cellular structure and the composition of the extracellular matrix of the aortic wall. The purpose of the present work was to study the cellular functions of endothelial and smooth muscle cells from the patients with aneurysms of the thoracic aorta. We studied endothelial and smooth muscle cells from aneurysms in patients with bicuspid aortic valve and with tricuspid aortic valve. The expression of key markers of endothelial (CD31, vWF, and VE-cadherin) and smooth muscle (SMA, SM22α, calponin, and vimentin) cells as well extracellular matrix and MMP activity was studied as well as and apoptosis and cell proliferation. Expression of functional markers of endothelial and smooth muscle cells was reduced in patient cells. Cellular proliferation, migration, and synthesis of extracellular matrix proteins are attenuated in the cells of the patients. We show for the first time that aortic endothelial cell phenotype is changed in the thoracic aortic aneurysms compared to normal aortic wall. In conclusion both endothelial and smooth muscle cells from aneurysms of the ascending aorta have downregulated specific cellular markers and altered functional properties, such as growth rate, apoptosis induction, and extracellular matrix synthesis.

Selective inhibition of Histone deacetylases reverses vascular remodelling and improves right ventricle function in pulmonary hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
K.B Kurakula ◽  
X.Q Sun ◽  
D.E Van Der Feen ◽  
Q.A.J Hagdorn ◽  
H.J Bogaard ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Right Ventricle ◽  
Smooth Muscle Cells ◽  
Histone Deacetylases ◽  
Vascular Remodeling ◽  
Muscle Cells ◽  
Selective Inhibition ◽  
Funding Source ◽  
Vascular Remodelling ◽  
Rv Function

Abstract Introduction Pulmonary arterial hypertension (PAH) is a progressive fatal disease characterized by abnormal remodelling of pulmonary vessels, leading to increased vascular resistance and right ventricle (RV) failure. This abnormal vascular remodelling is associated with endothelial cell dysfunction, increased proliferation of smooth muscle cells, inflammation, and disturbed transforming growth factor beta (TGF-β) signalling. Histone deacetylases (HDACs) have been shown to promote proliferation and inflammation in vascular cells. Although inhibition of HDACs using small molecule inhibitors attenuated vascular remodeling, these inhibitors worsened RV function in animal models of PAH. Therefore, we aim to validate Quisinostat, a selective inhibitor of HDACs whether it could reverse vascular remodeling in the lungs and improves RV function. Objective To determine the effect of Quisinostat on vascular remodelling and RV function in PAH. Methods and results We found that HDAC1 expression is increased in lungs of PAH patients. Inhibition of HDACs activity by Quisinostat significantly decreased TGF-β signaling and strongly decreased proliferation and inflammation in microvascular endothelial cells (MVECs). In addition, conditioned medium from Quisinostat treated PAH MVECs inhibited the growth of healthy smooth muscle cells. Quisinostat reversed abnormal vascular remodelling in the MCT-shunt and Sugen Hypoxia rat models of severe angioproliferative PAH, and improved RV function. Finally, Quisinostat improved the RV function in rats with RV pressure load induced by pulmonary artery banding. Importantly, Quisinostat exhibited no systemic and cardio toxic effects in vivo. Conclusions Our data demonstrate that selective inhibition of HDACs reverses vascular remodeling in the lungs and improves RV function. These data support the establishment of a clinical trial with Quisinostat in patients with PAH. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Dutch Lung Foundation

scholarly journals Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve disease

EBioMedicine ◽  
2019 ◽  
Vol 43 ◽  
pp. 54-66 ◽  
Author(s):  
Brittany Balint ◽  
Hao Yin ◽  
Zengxuan Nong ◽  
John-Michael Arpino ◽  
Caroline O'Neil ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Smooth Muscle Cells ◽  
Bicuspid Aortic Valve ◽  
Aortic Valve Disease ◽  
Muscle Cells ◽  
Ascending Aorta ◽  
Valve Disease

Dynamically-Loaded 3-D Model to Study the ECM Organization of Aortic Smooth Muscle Cells in Aneurysmal Patients With Bicuspid Aortic Valve

2011 ◽  
Author(s):  
Wei He ◽  
Julie Phillippi ◽  
Christopher E. Miller ◽  
David A. Vorp ◽  
Thomas G. Gleason
Keyword(s):  
Smooth Muscle ◽  
Aortic Valve ◽  
Smooth Muscle Cells ◽  
Bicuspid Aortic Valve ◽  
Elective Surgery ◽  
Muscle Cells ◽  
The United States ◽  
Aortic Aneurysms ◽  
Aortic Replacement ◽  
Valvular Stenosis

Rupture of aortic aneurysms and dissections are the fifteenth leading cause of a death in the United States [1]. Over 40% of patients undergoing elective surgery for ascending aortic replacement due to thoracic aortic aneurysm (TAA) have a congenital defect in the aortic valve know as bicuspid aortic valve (BAV) [2]. BAV patients have uniformly larger diameter aortic roots and ascending aortas compared to age- and sex-matched controls [3] and abnormal elasticity even in the absence of valvular stenosis or aneurysm [4] and this greatly increases the risk of aortic dissection and sudden death [5]. The cause of TAA is uncertain, but recent studies suggest that oxidative stress may play a role in the pathogenesis of TAAs by degrading the extracellular matrix (ECM). We identified that BAV smooth muscle cells (SMCs) lack sufficient resistance to reactive oxygen species to maintain ECM homeostasis [6, 7].

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