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Experimental Right Ventricular Hypertension Induces Regional β1-Integrin-Mediated Transduction of Hypertrophic and Profibrotic Right and Left Ventricular Signaling.
J Am Heart Assoc. 2018 03 29; 7(7)JA

Abstract

BACKGROUND

Development of right ventricular (RV) hypertension eventually contributes to RV and left ventricular (LV) myocardial fibrosis and dysfunction. The molecular mechanisms are not fully elucidated.

METHODS AND RESULTS

Pulmonary artery banding was used to induce RV hypertension in rats in vivo. Then, we evaluated cardiac function and regional remodeling 6 weeks after pulmonary artery banding. To further elucidate mechanisms responsible for regional cardiac remodeling, we also mimicked RV hypertensive stress by cyclic mechanical stretching applied to confluent cultures of cardiac fibroblasts, isolated from the RV free wall, septal hinge points, and LV free wall. Echocardiography and catheter evaluation demonstrated that rats in the pulmonary artery banding group developed RV hypertension with leftward septal displacement, LV compression, and increased LV end-diastolic pressures. Picrosirius red staining indicated that pulmonary artery banding induced marked RV fibrosis and dysfunction, with prominent fibrosis and elastin deposition at the septal hinge points but less LV fibrosis. These changes were associated with proportionally increased expressions of integrin-β1 and profibrotic signaling proteins, including phosphorylated Smad2/3 and transforming growth factor-β1. Moreover, mechanically stretched fibroblasts also expressed significantly increased levels of α-smooth muscle actin, integrin-β1, transforming growth factor-β1, collagen I deposition, and wrinkle formation on gel assays, consistent with myofibroblast transformation. These changes were not observed in parallel cultures of mechanically stretched fibroblasts, preincubated with the integrin inhibitor (BTT-3033).

CONCLUSIONS

Experimentally induced RV hypertension triggers regional RV, hinge-point, and LV integrin β1-dependent mechanotransduction signaling pathways that eventually trigger myocardial fibrosis via transforming growth factor-β1 signaling. Reduced LV fibrosis and preserved global function, despite geometrical and pressure aberrations, suggest a possible elastin-mediated protective mechanism at the septal hinge points.

Authors+Show Affiliations

Division of Cardiology, Labatt Family Heart Center, Toronto, Ontario, Canada. Translational Medicine, Hospital for Sick Children and University of Toronto, Ontario, Canada.Division of Cardiology, Labatt Family Heart Center, Toronto, Ontario, Canada. Translational Medicine, Hospital for Sick Children and University of Toronto, Ontario, Canada.Division of Cardiology, Labatt Family Heart Center, Toronto, Ontario, Canada. Translational Medicine, Hospital for Sick Children and University of Toronto, Ontario, Canada.The Keenan Research Center for Biomedical Science, St Michael's Hospital, Toronto, Canada.The Keenan Research Center for Biomedical Science, St Michael's Hospital, Toronto, Canada.Division of Cardiology, Labatt Family Heart Center, Toronto, Ontario, Canada. Translational Medicine, Hospital for Sick Children and University of Toronto, Ontario, Canada.Translational Medicine, Hospital for Sick Children and University of Toronto, Ontario, Canada.Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Ontario, Canada.Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Ontario, Canada.The Keenan Research Center for Biomedical Science, St Michael's Hospital, Toronto, Canada.The Keenan Research Center for Biomedical Science, St Michael's Hospital, Toronto, Canada.Division of Cardiology, Labatt Family Heart Center, Toronto, Ontario, Canada mark.friedberg@sickkids.ca. Translational Medicine, Hospital for Sick Children and University of Toronto, Ontario, Canada.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29599211

Citation

Sun, Mei, et al. "Experimental Right Ventricular Hypertension Induces Regional β1-Integrin-Mediated Transduction of Hypertrophic and Profibrotic Right and Left Ventricular Signaling." Journal of the American Heart Association, vol. 7, no. 7, 2018.
Sun M, Ishii R, Okumura K, et al. Experimental Right Ventricular Hypertension Induces Regional β1-Integrin-Mediated Transduction of Hypertrophic and Profibrotic Right and Left Ventricular Signaling. J Am Heart Assoc. 2018;7(7).
Sun, M., Ishii, R., Okumura, K., Krauszman, A., Breitling, S., Gomez, O., Hinek, A., Boo, S., Hinz, B., Connelly, K. A., Kuebler, W. M., & Friedberg, M. K. (2018). Experimental Right Ventricular Hypertension Induces Regional β1-Integrin-Mediated Transduction of Hypertrophic and Profibrotic Right and Left Ventricular Signaling. Journal of the American Heart Association, 7(7). https://doi.org/10.1161/JAHA.117.007928
Sun M, et al. Experimental Right Ventricular Hypertension Induces Regional β1-Integrin-Mediated Transduction of Hypertrophic and Profibrotic Right and Left Ventricular Signaling. J Am Heart Assoc. 2018 03 29;7(7) PubMed PMID: 29599211.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Experimental Right Ventricular Hypertension Induces Regional β1-Integrin-Mediated Transduction of Hypertrophic and Profibrotic Right and Left Ventricular Signaling. AU - Sun,Mei, AU - Ishii,Ryo, AU - Okumura,Kenichi, AU - Krauszman,Adrienn, AU - Breitling,Siegfried, AU - Gomez,Olga, AU - Hinek,Aleksander, AU - Boo,Stellar, AU - Hinz,Boris, AU - Connelly,Kim A, AU - Kuebler,Wolfgang M, AU - Friedberg,Mark K, Y1 - 2018/03/29/ PY - 2018/3/31/entrez PY - 2018/3/31/pubmed PY - 2019/11/2/medline KW - fibrosis KW - integrin KW - pressure overload KW - regional stress JF - Journal of the American Heart Association JO - J Am Heart Assoc VL - 7 IS - 7 N2 - BACKGROUND: Development of right ventricular (RV) hypertension eventually contributes to RV and left ventricular (LV) myocardial fibrosis and dysfunction. The molecular mechanisms are not fully elucidated. METHODS AND RESULTS: Pulmonary artery banding was used to induce RV hypertension in rats in vivo. Then, we evaluated cardiac function and regional remodeling 6 weeks after pulmonary artery banding. To further elucidate mechanisms responsible for regional cardiac remodeling, we also mimicked RV hypertensive stress by cyclic mechanical stretching applied to confluent cultures of cardiac fibroblasts, isolated from the RV free wall, septal hinge points, and LV free wall. Echocardiography and catheter evaluation demonstrated that rats in the pulmonary artery banding group developed RV hypertension with leftward septal displacement, LV compression, and increased LV end-diastolic pressures. Picrosirius red staining indicated that pulmonary artery banding induced marked RV fibrosis and dysfunction, with prominent fibrosis and elastin deposition at the septal hinge points but less LV fibrosis. These changes were associated with proportionally increased expressions of integrin-β1 and profibrotic signaling proteins, including phosphorylated Smad2/3 and transforming growth factor-β1. Moreover, mechanically stretched fibroblasts also expressed significantly increased levels of α-smooth muscle actin, integrin-β1, transforming growth factor-β1, collagen I deposition, and wrinkle formation on gel assays, consistent with myofibroblast transformation. These changes were not observed in parallel cultures of mechanically stretched fibroblasts, preincubated with the integrin inhibitor (BTT-3033). CONCLUSIONS: Experimentally induced RV hypertension triggers regional RV, hinge-point, and LV integrin β1-dependent mechanotransduction signaling pathways that eventually trigger myocardial fibrosis via transforming growth factor-β1 signaling. Reduced LV fibrosis and preserved global function, despite geometrical and pressure aberrations, suggest a possible elastin-mediated protective mechanism at the septal hinge points. SN - 2047-9980 UR - https://www.unboundmedicine.com/medline/citation/29599211/Experimental_Right_Ventricular_Hypertension_Induces_Regional_β1_Integrin_Mediated_Transduction_of_Hypertrophic_and_Profibrotic_Right_and_Left_Ventricular_Signaling_ L2 - http://www.ahajournals.org/doi/full/10.1161/JAHA.117.007928?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -