Treatment with a DC-SIGN ligand reduces macrophage polarization and diastolic dysfunction in the aging female but not ma
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ORIGINAL ARTICLE
Treatment with a DC-SIGN ligand reduces macrophage polarization and diastolic dysfunction in the aging female but not male mouse hearts JoAnn Trial & Rodrigo Diaz Lankenau & Aude Angelini & Jorge E. Tovar Perez & George E. Taffet & Mark L. Entman & Katarzyna A. Cieslik Received: 6 May 2020 / Accepted: 13 August 2020 # The Author(s) 2020
Abstract Cardiac diastolic dysfunction in aging arises from increased ventricular stiffness caused by inflammation and interstitial fibrosis. The diastolic dysfunction contributes to heart failure with preserved ejection fraction (HFpEF), which in the aging population is more common in women. This report examines its progression over 12 weeks in aging C57BL/6J mice and correlates its development with changes in macrophage polarization and collagen deposition. Aged C57BL/6J mice were injected with dendritic cell–specific intercellular adhesion molecule-3grabbing nonintegrin (DC-SIGN) ligand 1 (DCSL1, an anti-inflammatory agent) or saline for 12 weeks. Echo and Doppler measurements were performed before and after 4 and 12 weeks of treatment. DCSL1 prevented the worsening of diastolic dysfunction over time in females Electronic supplementary material The online version of this article (https://doi.org/10.1007/s11357-020-00255-4) contains supplementary material, which is available to authorized users. J. Trial : R. Diaz Lankenau : A. Angelini : J. E. Tovar Perez : G. E. Taffet : M. L. Entman : K. A. Cieslik (*) Department of Medicine, Cardiovascular Research, Baylor College of Medicine, One Baylor Plaza, MS: BCM 620, Houston, TX 77030, USA e-mail: [email protected] J. E. Tovar Perez Texas A&M University, 2121 W. Holcombe Blvd, Houston, TX 77030, USA G. E. Taffet : M. L. Entman The DeBakey Heart Center, Houston Methodist Hospital, 6565 Fannin Street, Houston, TX 77030, USA
but not in males. Cardiac single cell suspensions analyzed by flow cytometry revealed changes in the inflammatory infiltrate: (1) in males, there was an increased total number of leukocytes with an increased proinflammatory profile compared with females and they did not respond to DCSL1; (2) by contrast, DCSL1 treatment resulted in a shift in macrophage polarization to an anti-inflammatory phenotype in females. Notably, DCSL1 preferentially targeted tumor necrosis factor-α (TNFα+) pro-inflammatory macrophages. The reduction in pro-inflammatory macrophage polarization was accompanied by a decrease in collagen content in the heart. Age-associated diastolic dysfunction in mice is more severe in females and is associated with unique changes in macrophage polarization in cardiac tissue. Treatment with DCSL1 mitigates the changes in inflammation, cardiac function, and fibrosis. The characteristics of diastolic dysfunction in aging female mice mimic similar changes in aging women. Keywords Aging . Heart . Macrophages . DC-SIGN . Fibrosis
Introduction In clinical studies, heart failure with preserved ejection fraction (HFpEF) in older women is preceded by left ventricular diastolic dysfunction [42]. Over 75%
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