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J Am Heart Assoc. 2014 Jun 10;3(3):e000670. doi: 10.1161/JAHA.113.000670.

Cardiac CD47 drives left ventricular heart failure through Ca2+-CaMKII-regulated induction of HDAC3.

Author information

1
Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (M.S.S., M.Q., J.B., S.F.S., H.C.C., J.S.I.) Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (M.S.S., H.C.C., J.S.I.).
2
Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA (A.H.S., H.C.C.).
3
Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (M.S.S., M.Q., J.B., S.F.S., H.C.C., J.S.I.).
4
Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA (M.M., M.R., C.M.S.C.).
5
Division of Cardiology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA (C.F.M.T.).
6
Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (R.A.B.).
7
Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA (M.S.S., M.Q., J.B., S.F.S., H.C.C., J.S.I.) Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA (M.S.S., H.C.C., J.S.I.) Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA (A.H.S., H.C.C.).

Abstract

BACKGROUND:

Left ventricular heart failure (LVHF) remains progressive and fatal and is a formidable health problem because ever-larger numbers of people are diagnosed with this disease. Therapeutics, while relieving symptoms and extending life in some cases, cannot resolve this process and transplant remains the option of last resort for many. Our team has described a widely expressed cell surface receptor (CD47) that is activated by its high-affinity secreted ligand, thrombospondin 1 (TSP1), in acute injury and chronic disease; however, a role for activated CD47 in LVHF has not previously been proposed.

METHODS AND RESULTS:

In experimental LVHF TSP1-CD47 signaling is increased concurrent with up-regulation of cardiac histone deacetylase 3 (HDAC3). Mice mutated to lack CD47 displayed protection from transverse aortic constriction (TAC)-driven LVHF with enhanced cardiac function, decreased cellular hypertrophy and fibrosis, decreased maladaptive autophagy, and decreased expression of HDAC3. In cell culture, treatment of cardiac myocyte CD47 with a TSP1-derived peptide, which binds and activates CD47, increased HDAC3 expression and myocyte hypertrophy in a Ca(2+)/calmodulin protein kinase II (CaMKII)-dependent manner. Conversely, antibody blocking of CD47 activation, or pharmacologic inhibition of CaMKII, suppressed HDAC3 expression, decreased myocyte hypertrophy, and mitigated established LVHF. Downstream gene suppression of HDAC3 mimicked the protective effects of CD47 blockade and decreased hypertrophy in myocytes and mitigated LVHF in animals.

CONCLUSIONS:

These data identify a proximate role for the TSP1-CD47 axis in promoting LVHF by CaKMII-mediated up-regulation of HDAC3 and suggest novel therapeutic opportunities.

KEYWORDS:

CD47; CaKMII; HDAC3; calcium; heart failure; thrombospondin‐1

PMID:
24922625
PMCID:
PMC4309049
DOI:
10.1161/JAHA.113.000670
[Indexed for MEDLINE]
Free PMC Article
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