Cardiac mast cells mediate left ventricular fibrosis in the hypertensive rat heart. Hypertension 2009 Jun;53(6):1041-7
Date
04/29/2009Pubmed ID
19398662DOI
10.1161/HYPERTENSIONAHA.108.123158Scopus ID
2-s2.0-67049100694 (requires institutional sign-in at Scopus site) 139 CitationsAbstract
Correlative data suggest that cardiac mast cells are a component of the inflammatory response that is important to hypertension-induced adverse myocardial remodeling. However, a causal relationship has not been established. We hypothesized that adverse myocardial remodeling would be inhibited by preventing the release of mast cell products that may interact with fibroblasts and other inflammatory cells. Eight-week-old male spontaneously hypertensive rats were treated for 12 weeks with the mast cell stabilizing compound nedocromil (30 mg/kg per day). Age-matched Wistar-Kyoto rats served as controls. Nedocromil prevented left ventricular fibrosis in the spontaneously hypertensive rat independent of hypertrophy and blood pressure, despite cardiac mast cell density being elevated. The mast cell protease tryptase was elevated in the spontaneously hypertensive rat myocardium and was normalized by nedocromil. Treatment of isolated adult spontaneously hypertensive rat cardiac fibroblasts with tryptase induced collagen synthesis and proliferation, suggesting this as a possible mechanism of mast cell-mediated fibrosis. In addition, nedocromil prevented macrophage infiltration into the ventricle. The inflammatory cytokines interferon-gamma and interleukin (IL)-4 were increased in the spontaneously hypertensive rat and normalized by nedocromil, whereas IL-6 and IL-10 were decreased in the spontaneously hypertensive rat, with nedocromil treatment normalizing IL-6 and increasing IL-10 above the control. These results demonstrate for the first time a causal relationship between mast cell activation and fibrosis in the hypertensive heart. Furthermore, these results identify several mechanisms, including tryptase, inflammatory cell recruitment, and cytokine regulation, by which mast cells may mediate hypertension-induced left ventricular fibrosis.
Author List
Levick SP, McLarty JL, Murray DB, Freeman RM, Carver WE, Brower GLMESH terms used to index this publication - Major topics in bold
Analysis of VarianceAnimals
Blotting, Western
Cell Proliferation
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Fibrosis
Hypertension
Hypertrophy, Left Ventricular
Immunohistochemistry
Male
Mast Cells
Nedocromil
Probability
Random Allocation
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Reference Values
Sensitivity and Specificity
