Immediate Hypersensitivity Elicits Renin Release from Cardiac Mast Cells

Abstract

Background: We recently reported that murine and cavian heart mast cells are a unique extrarenal source of renin. Ischemia/reperfusion releases this renin leading to local angiotensin formation and norepinephrine release. As mast cells are a primary target of hypersensitivity, we assessed whether anaphylactic mast cell degranulation also results in renin and norepinephrine release. Methods: Hearts isolated from presensitized guinea pigs were challenged with antigen. Results: Cardiac anaphylaxis was characterized by mast cell degranulation, evidenced by β-hexosaminidase release and associated with renin and norepinephrine release. Mast cell stabilization with cromolyn or lodoxamide markedly attenuated the release of β-hexosaminidase, renin and norepinephrine. Renin inhibition with BILA2157 did not affect mast cell degranulation, but attenuated norepinephrine release. Conclusions: Our findings disclose that immediate-type hypersensitivity elicits renin release from mast cells, activating a local renin-angiotensin system, thereby promoting norepinephrine release. As renin is stored in human heart mast cells, allergic reactions could initiate renin release, leading to local angiotensin formation and hyperadrenergic dysfunction.

Targeting Cardiac Mast Cells: Pharmacological Modulation of the Local Renin-Angiotensin System

“…Second, mast cell degranulation can be prevented by blocking the effect of mast cell-degranulating peptides at their receptors on the mast cell membrane (e.g., with Substance P and CGRP receptor antagonists)[13]. Third, mast cell degranulation can be prevented with mast cell stabilizers (e.g., disodium cromoglycate and related agents)[6,19]. Fourth, mast cell-degranulating ROS and toxic aldehydes which are produced in ischemia-reperfusion can be eliminated by agents that directly and selectively activate aldehyde dehydrogenase type-2 (ALDH2) in mast cell mitochondria [9].…”

“…This is unlike the guinea pig and mouse heart, in which not only 48/80, but also ischemia/reperfusion, immediate hypersensitivity reactions, toxic aldehydes and reactive oxygen species, as well as mast cell-degranulating neuropeptides, elicit the release of renin activity in the coronary effluent, in association with norepinephrine release and reperfusion arrhythmias [6,9,13,19]. These arrhythmias, which do not occur in the mast cell-deficient mouse heart, are the result of local RAS activation; indeed, they are sensitive to mast cell stabilization, direct renin inhibition and ANG II type 1 receptor blockade [6,33].…”

Mast Cell Proteases as Protective and Inflammatory Mediators

“…Studies by Mackins and colleagues 89, 90 establish that mast cells can store renin, which is released by mast cell activators like compound 48/80 and allergen and boosts local generation of angiotensin I, which is then processed to angiotensin II by ACE or chymase-like peptidases. Presumably, mast cell renin could serve homeostatic functions, although existing studies focus on potential pathological contributions.…”

Adenosine A2Areceptor activation reduces infarct size in the isolated, perfused mouse heart by inhibiting resident cardiac mast cell degranulation

“…In the heart, degranulation of resident cardiac mast cells mediates injurious effects during experimental ischemia-reperfusion (I/R) injury and myocardial infarction (MI). These deleterious effects are mediated by multiple mechanisms, including a local renin-angiotensin axis (18,26,41), histamine and prostanoid-induced ventricular arrhythmogenesis (36), and the initiation of a cytokine cascade resulting in increased ICAM-1 expression and neutrophil extravasation (13,42). In addition, resident cardiac mast cells contribute to the ventricular hypertrophic response during chronic cardiac volume overload (6,16,32,33).…”