Background-Renin released by ischemia/reperfusion from cardiac mast cells activates a local renin-angiotensin system (RAS). This exacerbates norepinephrine release and reperfusion arrhythmias (ventricular tachycardia and fibrillation), making RAS a new therapeutic target in myocardial ischemia. Methods and Results-We investigated whether ischemic preconditioning (IPC) prevents cardiac RAS activation in guinea pig hearts ex vivo. When ischemia/reperfusion (20 minutes of ischemia/30 minutes of reperfusion) was preceded by IPC (two 5-minute ischemia/reperfusion cycles), renin and norepinephrine release and ventricular tachycardia and fibrillation duration were markedly decreased, a cardioprotective anti-RAS effect. Activation and blockade of adenosine A 2b /A 3 receptors and activation and inhibition of protein kinase C⑀ (PKC⑀) mimicked and prevented, respectively, the anti-RAS effects of IPC. Moreover, activation of A 2b /A 3 receptors or activation of PKC⑀ prevented degranulation and renin release elicited by peroxide in cultured mast cells (HMC-1). Activation and inhibition of mitochondrial aldehyde dehydrogenase type-2 (ALDH2) also mimicked and prevented, respectively, the cardioprotective anti-RAS effects of IPC. Furthermore, ALDH2 activation inhibited degranulation and renin release by reactive aldehydes in HMC-1. Notably, PKC⑀ and ALDH2 were both activated by A 2b /A 3 receptor stimulation in HMC-1, and PKC⑀ inhibition prevented ALDH2 activation. Conclusions-The

We previously reported that mast cells express renin, the ratelimiting enzyme in the renin-angiotensin cascade. We have now assessed whether mast cell renin release triggers angiotensin formation in the airway. In isolated rat bronchial rings, mast cell degranulation released enzyme with angiotensin I-forming activity blocked by the selective renin inhibitor BILA2157. Local generation of angiotensin (ANG II) from mast cell renin elicited bronchial smooth muscle contraction mediated by ANG II type 1 receptors (AT 1R). In a guinea pig model of immediate type hypersensitivity, anaphylactic mast cell degranulation in bronchial rings resulted in ANG II-mediated constriction. As in rat bronchial rings, bronchoconstriction (BC) was inhibited by a renin inhibitor, an AT 1R blocker, and a mast cell stabilizer. Anaphylactic release of renin, histamine, and ␤-hexosaminidase from mast cells was confirmed in the effluent from isolated, perfused guinea pig lung. To relate the significance of this finding to humans, mast cells were isolated from macroscopically normal human lung waste tissue specimens. Sequence analysis of human lung mast cell RNA showed 100% homology between human lung mast cell renin and kidney renin between exons 1 and 10. Furthermore, the renin protein expressed in lung mast cells was enzymatically active. Our results demonstrate the existence of an airway renin-angiotensin system triggered by release of mast-cell renin. The data show that locally produced ANG II is a critical factor governing BC, opening the possibility for novel therapeutic targets in the management of airway disease.angiotensin II ͉ angiotensin II type 1 receptors ͉ asthma ͉ hypersensitivity ͉ lung T he renin-angiotensin system (RAS) has been traditionally viewed as a circulating axis, whereby renin is released into the circulation from the kidneys in response to decreased renal perfusion pressure, decreased delivery of NaCl at the macula densa, and/or increased renal sympathetic nerve activity (1). The proteolytic cleavage of angiotensinogen (aogen) by renin constitutes the rate-limiting step of the RAS cascade.In addition to this classical view, it is believed that many tissues, including the lung, may possess the capacity to generate angiotensin (ANG II) locally (2, 3). This is supported by experiments demonstrating that ANG II persists in lung of nephrectomized rats (4) and findings showing that ANG II can be elevated in the lungs in the absence of an elevated systemic RAS (5). Components of RAS have been identified in lung tissue, including aogen mRNA (6, 7), and angiotensin-converting enzyme (ACE), the pulmonary endothelium being the primary source for ACE in the body (8). ANG II receptors are also expressed in lung tissue, with the ANG II type 1 receptor (AT 1 R) subtype found on bronchial smooth muscle cells (9) and ANG II type 2 receptor (AT 2 R) observed on the bronchial epithelial cell brush border (10). An intrapulmonary source of renin protein has not yet been identified.We previously reported that mast cells synthesize, st...

Renin released by ischemia/reperfusion (I/R) from cardiac mast cells (MCs) activates a local renin-angiotensin system (RAS) causing arrhythmic dysfunction. Ischemic preconditioning (IPC) inhibits MC renin release and consequent activation of this local RAS. We postulated that MC histamine H 4 -receptors (H 4 Rs), being Ga i/o -coupled, might activate a protein kinase C isotype-« (PKC«)-aldehyde dehydrogenase type-2 (ALDH2) cascade, ultimately eliminating MC-degranulating and renin-releasing effects of aldehydes formed in I/R and associated arrhythmias. We tested this hypothesis in ex vivo hearts, human mastocytoma cells, and bone marrow-derived MCs from wild-type and H 4 R knockout mice. We found that activation of MC H 4 Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKC« and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H 4 R agonists and disappear when H 4 Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H 4 Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKC« and ALDH2 activation, reduction of toxic aldehyde-induced MC renin release, prevention of RAS activation, reduction of norepinephrine release, and ultimately to alleviation of reperfusion arrhythmias. This newly discovered protective pathway suggests that MC H 4 Rs may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.

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.