Abstract 20471: Thrombospondin-4 is a Key Mediator in Cardiac Aging
Thrombospondin-4 (TSP4) is a matricellular protein that is essential for the heart to adapt to stress. We previously demonstrated that mice lacking TSP4 develop heart failure (HF) when exposed to high blood pressure, the latter phenomenon being secondary to deficient extracellular matrix (ECM)-myocyte crosstalk. In the present study we tested the hypothesis that TSP4 is also a key mediator in cardiac aging. TSP4-/- mice and controls (WT) were followed for almost 3 years. TSP4 expression increased with aging as well as with exercise. TSP4-/- died at a younger age than WT (Kaplan-Meyer curve; p= 0.001). TSP4-/- developed HF (LVEF = 58 ± 12 vs 38 ± 14 %, for WT and TSP4-/-; p< 0.05), and a phenotype characterized by obesity, sedentarism and cardiac fibrosis. A subgroup of old (24 months of age) TSP4-/- and WT animals (N= 8 each) were exposed to intense exercise (treadmill twice daily for 8 weeks). WT mice improved cardiac contractility and LV mass with exercise as opposed to TSP4-/- animals that failed to do so (echo and cardiac pressure-volume analysis; p < 0.05 for LVEF, PRSW and dP/dt/IP, WT vs. TSP4-/-). Isolated cardiac myocyte studies from these animals showed that TSP4-/- contractility and calcium transients failed to augment with isoproterenol p<0.02 WT vs TSP4-/-). Phosphorylation of AMPK was increased in TSP4 -/- hearts, together with phosphorylation of GSK-3 alpha and beta isoforms, effects that seem to be mediated through an interaction between TSP4 and the CD 44 receptor. We report for the first time that TSP4 is essential for aging. Lack of this protein shortens lifespan in mice and reveals a phenotype of decreased cardiac contractility, increased cardiac interstitial fibrosis, with decreased myocyte calcium transients. These effects are present in the isolated myocyte (ECM-independent) and seem to involve AMPK and GSK-3.
Author Disclosures: D.I. Lee: None. S.S. Yu: None. D. Bedja: None. D.A. Kass: None. O.H. Cingolani: None.
- © 2014 by American Heart Association, Inc.