Histamine H₄-Receptors Inhibit Mast Cell Renin Release in Ischemia/Reperfusion via Protein Kinase Cε-Dependent Aldehyde Dehydrogenase Type-2 Activation

Abstract

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.

Relation of Polymorphism of the Histidine Decarboxylase Gene to Chronic Heart Failure in Han Chinese

“…8 In addition, besides these direct effects on myocardial cells, cardiac histamine was also reported to exert indirect modulating effects on cardiac local rennineangiotensin system (RAS) and hence on myocardial remodeling through histamine H 3 and H 4 receptors. 27,28 These lines of evidence agree with the present observation that the level of histamine in failing hearts has an impact on the pathophysiology of CHF and is associated with CHF risk.…”

Human mast cells and basophils—How are they similar how are they different?

“…H4R expression has been shown on human mast cells and basophils . H4R activation can modulate the function of mast cells and basophils …”

International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors

“…Furthermore, these cells responded to 4-methylhistamine with ERK and PI3K activation as well as the production of a variety of inflammatory mediators such as IL-6 (Jemima et al, 2014). In ex vivo animal models, human mastocytoma cells and bone marrow-derived murine mast cells, H 4 receptor activation resulted in inhibition of renin release via activation of protein kinase C isotype-« and aldehyde dehydrogenase type-2 (Aldi et al, 2014).…”