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

Maryam Sharifi-Sanjani1, Ali Hakim Shoushtari2, Marisol Quiroz3

  • 1Vascular 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.).

Journal of the American Heart Association
|June 13, 2014
PubMed

Insights

The thrombospondin 1 (TSP1)-CD47 pathway promotes left ventricular heart failure (LVHF) by increasing histone deacetylase 3 (HDAC3). Blocking this pathway offers a novel therapeutic strategy for LVHF.

Area of Science:

  • Cardiovascular Biology
  • Molecular Cardiology
  • Cell Signaling

Background:

  • Left ventricular heart failure (LVHF) is a progressive, fatal condition with limited therapeutic options.
  • The cell surface receptor CD47, activated by thrombospondin 1 (TSP1), is implicated in various diseases but its role in LVHF was unknown.

Purpose of the Study:

  • To investigate the role of the TSP1-CD47 axis in the development of LVHF.
  • To explore the downstream signaling pathways involved in TSP1-CD47-mediated cardiac dysfunction.

Main Methods:

  • Utilized a mouse model of transverse aortic constriction (TAC) to induce LVHF.
  • Examined TSP1-CD47 signaling, cardiac histone deacetylase 3 (HDAC3) expression, and Ca(2+)/calmodulin protein kinase II (CaMKII) activity.
  • Employed cell culture experiments with cardiac myocytes and in vivo interventions including CD47 blocking antibodies and HDAC3 inhibition.

Main Results:

  • TSP1-CD47 signaling and HDAC3 expression were elevated in experimental LVHF.
  • Mice lacking CD47 were protected from TAC-induced LVHF, showing improved cardiac function and reduced hypertrophy and fibrosis.
  • CD47 activation in myocytes increased HDAC3 and hypertrophy via CaMKII; blocking CD47 or CaMKII mitigated these effects and LVHF.

Conclusions:

  • The TSP1-CD47 axis promotes LVHF through CaMKII-mediated upregulation of HDAC3.
  • Targeting the TSP1-CD47-CaMKII-HDAC3 pathway presents a novel therapeutic avenue for LVHF.
Abstract

Keywords:
CD47CaKMIIHDAC3calciumheart failurethrombospondin‐1

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