Our preliminary studies have identified two original cardioprotective effects of histamine H3-receptor activation. These are: 1) The mimicking of a new paradigm of ischemic preconditioning, which prevents the activation of a local mast cell-dependent renin- angiotensin system (RAS) and its dysfunctional consequences;and, 2) The inhibition of a previously unsuspected pro-adrenergic effect of cardiac natriuretic peptides. An in- depth exploration of these novel H3-receptor-mediated cardioprotective effects is the main goal of this application.
Aim I seeks to define: a) how ischemic preconditioning prevents the activation of the mast cell-dependent RAS, thus alleviating norepinephrine- and angiotensin-induced arrhythmias;and, b) how H3-receptor activation mimics the cardioprotective anti-RAS effects of preconditioning. The contribution of adenosine A2b/A3-receptors, protein kinase C5 (PKC5) and aldehyde dehydrogenase type-2 (ALDH2) to preconditioning-mediated anti-RAS effects will be studied in isolated guinea- pig and PKC5-/- mouse hearts subjected to ischemia/reperfusion, and in cultured mast cell, both wild-type and depleted of PKC5 and ALDH2 by siRNA technology. The capacity of H3-receptors to inhibit the release of mast cell-degranulating neuropeptides from in isolated hearts. Roles of PKC2I, 7 and 8 in inhibiting mast cell degranulation will be studied in mast cell cultures.
Aim II seeks to determine by which mechanisms natriuretic peptides exert a pro- adrenergic effect and how this is inhibited by H3-receptor activation. We will assess whether the catecholamine-releasing effects of natriuretic peptides derive from a cGMP/PKG-mediated prevention of cAMP hydrolysis by PDE3 and whether H3-receptor activation limits these proadrenergic effects by inhibiting PKG and/or stimulating PDE3. Isolated hearts, sympathetic nerve endings and PC12 cells, both wild-type and PKG- and PDE3-depleted by siRNA, will be used. Collectively, these studies will elucidate new mechanisms for the control of renin and norepinephrine release in the heart. As the search for effective cardioprotective drugs continues unabated, our proposed studies will foster the design of new agents (e.g., selective H3-receptor agonists) mimicking the beneficial effects of preconditioning and enabling a safe and effective treatment of congestive heart failure with natriuretic peptides. and ATP sensory/sympathetic nerves will be assessed

Public Health Relevance

A critical goal in myocardial ischemia and heart failure is to reduce renin and norepinephrine release directly in the heart, in order to decrease the high morbidity and mortality associated with these conditions. The general objective of this investigation is to elucidate novel mechanisms of cardioprotection designed to attenuate the local release of renin and norepinephrine and alleviate cardiac dysfunction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
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Wang, Lan-Hsiang
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Marino, Alice; Sakamoto, Takuya; Robador, Pablo A et al. (2017) S1P receptor 1-Mediated Anti-Renin-Angiotensin System Cardioprotection: Pivotal Role of Mast Cell Aldehyde Dehydrogenase Type 2. J Pharmacol Exp Ther 362:230-242
Marino, Alice; Martelli, Alma; Citi, Valentina et al. (2016) The novel H2 S donor 4-carboxy-phenyl isothiocyanate inhibits mast cell degranulation and renin release by decreasing intracellular calcium. Br J Pharmacol 173:3222-3234
Aldi, Silvia; Marino, Alice; Tomita, Kengo et al. (2015) E-NTPDase1/CD39 modulates renin release from heart mast cells during ischemia/reperfusion: a novel cardioprotective role. FASEB J 29:61-9
Aldi, Silvia; Takano, Ken-ichi; Tomita, Kengo et al. (2014) Histamine H4-receptors inhibit mast cell renin release in ischemia/reperfusion via protein kinase C ?-dependent aldehyde dehydrogenase type-2 activation. J Pharmacol Exp Ther 349:508-17
Hu, Zhaoyang; Crump, Shawn M; Anand, Marie et al. (2014) Kcne3 deletion initiates extracardiac arrhythmogenesis in mice. FASEB J 28:935-45
Aldi, Silvia; Robador, Pablo A; Tomita, Kengo et al. (2014) IgE receptor-mediated mast-cell renin release. Am J Pathol 184:376-81
Chan, Noel Yan-Ki; Robador, Pablo A; Levi, Roberto (2012) Natriuretic peptide-induced catecholamine release from cardiac sympathetic neurons: inhibition by histamine H3 and H4 receptor activation. J Pharmacol Exp Ther 343:568-77
Robador, Pablo A; Seyedi, Nahid; Chan, Noel Yan-Ki et al. (2012) Aldehyde dehydrogenase type 2 activation by adenosine and histamine inhibits ischemic norepinephrine release in cardiac sympathetic neurons: mediation by protein kinase C?. J Pharmacol Exp Ther 343:97-105
Hashikawa-Hobara, Narumi; Chan, Noel Yan-Ki; Levi, Roberto (2012) Histamine 3 receptor activation reduces the expression of neuronal angiotensin II type 1 receptors in the heart. J Pharmacol Exp Ther 340:185-91
Chan, Noel Yan-Ki; Seyedi, Nahid; Takano, Kenichi et al. (2012) An unsuspected property of natriuretic peptides: promotion of calcium-dependent catecholamine release via protein kinase G-mediated phosphodiesterase type 3 inhibition. Circulation 125:298-307

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