A role for cardiac mast cells in the pathogenesis of hypertensive heart disease

OBJECTIVE: Cardiac mast cells participate in myocardial dysfunction, but the mechanisms are presently unknown. DESIGN: By examining spontaneously hypertensive rats (SHRs) during their entire lifespan, we attempted to define the role of mast cells in the induction of cardiac hypertrophy and transition to heart failure. METHODS AND RESULTS: By contrast to normotensive littermates, hearts of newborn SHRs already contained mast cells. In the prehypertensive (2-week-old) SHRs, the increased expression of c-kit and soluble stem cell factor correlated with an increased number of cardiac mast cells. The mast cells contained tumour necrosis factor-alpha which, together with nuclear factor kappa-B (NF-kappaB) and interleukin (IL)-6, was significantly induced in the prehypertensive SHRs. Stimulation of cardiac mast cells with compound 48/80 in an ex-vivo Langendorff heart perfusion system resulted in increased expression of nuclear factor Kappa-B (NF-kappaB) (four-fold) and IL-6 (nine-fold) mRNA in the left ventricles of adult rat hearts. In the presence of an inhibitor of mast cell degranulation, disodium cromoglycate, the induced expression of NF-kappaB and IL-6 was inhibited. In the late hypertensive stage, the hearts of SHRs with advanced cardiac hypertrophy (12-month-old) and heart failure (20-month-old) had significantly increased levels of transforming growth factor (TGF)-beta1 and basic fibroblast growth factor (bFGF), and displayed increased myocardial fibrosis. Activated mast cells were a major source of TGF-beta1 and bFGF, and localized to areas of myocardial fibrosis. CONCLUSIONS: By synthesizing and secreting prohypertrophic cytokines and profibrotic growth factors, cardiac mast cells participate in the induction of cardiac hypertrophy and cardiac fibrosis, which are the key steps in the transition to heart failure.