Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via protein kinase C ε-dependent aldehyde dehydrogenase type-2 activation.
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 H4-receptors (H4Rs), being Gαi/o-coupled, might activate a protein kinase C isotype-ε (PKCε)-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 H4R knockout mice. We found that activation of MC H4Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKCε and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H4R agonists and disappear when H4Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H4Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKCε 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 H4Rs 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.
Department of Pharmacology, Weill Cornell Medical College, New York, New York, (S.A., K.-i.T., K.T., K.K., N.C., A.M., M.S.-R., R.L.); and Department of Immunology, Janssen Research & Development, L.L.C., San Diego, California (R.L.T.).
Silvia
S
Aldi
Ken-ichi
K
Takano
Kengo
K
Tomita
Kenichiro
K
Koda
Noel Y-K
NY
Chan
Alice
A
Marino
Mariselis
M
Salazar-Rodriguez
Robin L
RL
Thurmond
Roberto
R
Levi
D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D004789:Enzyme Activation; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D019194:Ischemic Preconditioning; D008407:Mast Cells / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D051744:Protein Kinase C-epsilon / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011968:Receptors, Histamine / Q000235:genetics / Q000378:metabolism*; D000074040:Receptors, Histamine H4; D012083:Renin / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology
C498829:Hrh4 protein, mouse; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C096127:ALDH2 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D051744:Protein Kinase C-epsilon; D012083:Renin