Granule cargo release from bone marrow-derived cells sustains cardiac hypertrophy

Am J Physiol Heart Circ Physiol. 2014 Nov 15;307(10):H1529-38. doi: 10.1152/ajpheart.00951.2013. Epub 2014 Sep 19.


Bone marrow-derived inflammatory cells, including platelets, may contribute to the progression of pressure overload-induced left ventricular hypertrophy (LVH). However, the underlying mechanisms for this are still unclear. One potential mechanism is through release of granule cargo. Unc13-d(Jinx) (Jinx) mice, which lack Munc13-4, a limiting factor in vesicular priming and fusion, have granule secretion defects in a variety of hematopoietic cells, including platelets. In the current study, we investigated the role of granule secretion in the development of LVH and cardiac remodeling using chimeric mice specifically lacking Munc13-4 in marrow-derived cells. Pressure overload was elicited by transverse aortic constriction (TAC). Chimeric mice were created by bone marrow transplantation. Echocardiography, histology staining, immunohistochemistry, real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and mass spectrometry were used to study LVH progression and inflammatory responses. Wild-type (WT) mice that were transplanted with WT bone marrow (WT→WT) and WT mice that received Jinx bone marrow (Jinx→WT) developed LVH and a classic fetal reprogramming response early (7 days) after TAC. However, at late times (5 wk), mice lacking Munc13-4 in bone marrow-derived cells (Jinx→WT) failed to sustain the cardiac hypertrophy observed in WT chimeric mice. No difference in cardiac fibrosis was observed at early or late time points. Reinjection of WT platelets or platelet releasate partially restored cardiac hypertrophy in Jinx chimeric mice. These results suggest that sustained LVH in the setting of pressure overload depends on one or more factors secreted from bone marrow-derived cells, possibly from platelets. Inhibiting granule cargo release may represent a novel target for preventing sustained LVH.

Keywords: Munc13-4; bone marrow-derived cells; granule secretion; platelet; pressure overload-induced left ventricular hypertrophy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blood Platelets / metabolism*
  • Bone Marrow Cells / metabolism*
  • Bone Marrow Transplantation
  • Disease Models, Animal
  • Hypertension / complications
  • Hypertrophy, Left Ventricular / etiology
  • Hypertrophy, Left Ventricular / metabolism*
  • Hypertrophy, Left Ventricular / pathology
  • Hypertrophy, Left Ventricular / prevention & control
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Platelet Transfusion
  • Secretory Vesicles / metabolism*
  • Time Factors
  • Ventricular Function, Left
  • Ventricular Remodeling


  • Membrane Proteins
  • Unc13d protein, mouse