Cardiac Mast Cells Mediate Left Ventricular Fibrosis in the Hypertensive Rat Heart

Abstract

Abstract-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-␥ 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.

Short-term ACE inhibition confers long-term protection against target organ damage

“…23 Fibroblasts may mediate the switch from acute inflammatory response to a situation of chronic inflammation. 24 Mast cells, 25 macrophages 26 and T cells 27 have all been found at the site of active remodeling and cytokines released from these cells can promote collagen deposition and fibroblast proliferation. In animal models of pressure overloadinduced LV hypertrophy, a transient increase in cytokine release and macrophage infiltration 28 has been shown, and Hsieh et al 29 have demonstrated that NOS inhibition with L-NAME in hypertensive rats increases vascular inflammation.…”

Oral sophocarpine protects rat heart against pressure overload-induced cardiac fibrosis

“…However, a convincing and potent antifibrogenic therapeutic modality by targeting myocardial local inflammation activation is still unavailable. Recent studies have indicated that an increase of myocardial proinflammatory mediator (i.e., interleukin-6, IL-6) levels and inflammatory cells infiltration preceded the occurrence of cardiac fibrosis in response to chronic pressure overload stress (Kudo et al, 2009;Levick et al, 2009Levick et al, , 2010.…”

Pathogenic role of mast cells in the development of diabetic nephropathy: a study of patients at different stages of the disease

“…Knowledge obtained in the past two decades indicates that MCs are not only the key effector cells in anaphylaxis, but also regulators of innate and adaptive immune responses [2,3]. The pathogenic roles of MCs have been extended to allergic diseases and helminth infection, and other diseases such as autoimmune diseases, inflammatory diseases, carcinogenesis and fibrosis [3][4][5][6][7][8][9][10]. With regards to the production of tryptase and chymase, two subtypes of MCs have been reported in humans: the MC T subtype is believed to produce tryptase only, whereas the MC TC subtype is believed to produce both tryptase and chymase.…”