Cardiovascular Protection by ApoE and ApoE-HDL Linked to Suppression of ECM Gene Expression and Arterial Stiffening
Devashish Kothapalli,
Shu-Lin Liu,
Yong Ho Bae,
James Monslow,
Tina Xu,
Elizabeth A. Hawthorne,
Fitzroy J. Byfield,
Paola Castagnino,
Shilpa Rao,
Daniel J. Rader,
Ellen Puré,
Michael C. Phillips,
Sissel Lund-Katz,
Paul A. Janmey,
Richard K. Assoian
Affiliations
Devashish Kothapalli
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
Shu-Lin Liu
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
Yong Ho Bae
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
James Monslow
Wistar Institute, Philadelphia, Philadelphia, PA 19104, USA
Tina Xu
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
Elizabeth A. Hawthorne
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
Fitzroy J. Byfield
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
Paola Castagnino
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
Shilpa Rao
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
Daniel J. Rader
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
Ellen Puré
Wistar Institute, Philadelphia, Philadelphia, PA 19104, USA
Michael C. Phillips
The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Sissel Lund-Katz
The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Paul A. Janmey
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
Richard K. Assoian
Institute for Translational Medicine and Therapeutics, Departments of Pharmacology, Medicine, and Physiology, and the Molecular Profiling Facility, University of Pennsylvania, Philadelphia, PA 19104, USA
Arterial stiffening is a risk factor for cardiovascular disease, but how arteries stay supple is unknown. Here, we show that apolipoprotein E (apoE) and apoE-containing high-density lipoprotein (apoE-HDL) maintain arterial elasticity by suppressing the expression of extracellular matrix genes. ApoE interrupts a mechanically driven feed-forward loop that increases the expression of collagen-I, fibronectin, and lysyl oxidase in response to substratum stiffening. These effects are independent of the apoE lipid-binding domain and transduced by Cox2 and miR-145. Arterial stiffness is increased in apoE null mice. This stiffening can be reduced by administration of the lysyl oxidase inhibitor BAPN, and BAPN treatment attenuates atherosclerosis despite highly elevated cholesterol. Macrophage abundance in lesions is reduced by BAPN in vivo, and monocyte/macrophage adhesion is reduced by substratum softening in vitro. We conclude that apoE and apoE-containing HDL promote healthy arterial biomechanics and that this confers protection from cardiovascular disease independent of the established apoE-HDL effect on cholesterol.
