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

Abstract

Enhanced production of angiotensin II and excessive release of norepinephrine in the ischemic heart are major causes of arrhythmias and sudden cardiac death. Mast cell-dependent mechanisms are pivotal in the local formation of angiotensin II and modulation of norepinephrine release in cardiac pathophysiology. Cardiac mast cells increase in number in myocardial ischemia and are located in close proximity to sympathetic neurons expressing angiotensin AT1- and histamine H3-receptors. Once activated, cardiac mast cells release a host of potent pro-inflammatory and pro-fibrotic cytokines, chemokines, preformed mediators (e.g., histamine) and proteases (e.g., renin). In myocardial ischemia, angiotensin II (formed locally from mast cell-derived renin) and histamine (also released from local mast cells) respectively activate AT1- and H3-receptors on sympathetic nerve endings. Stimulation of angiotensin AT1-receptors is arrhythmogenic whereas H3-receptor activation is cardioprotective. It is likely that in ischemia/reperfusion the balance may be tipped toward the deleterious effects of mast cell renin, as demonstrated in mast cell-deficient mice, lacking mast cell renin and histamine in the heart. In these mice, no ventricular fibrillation occurs at reperfusion following ischemia, as opposed to wild-type hearts which all fibrillate. Preventing mast cell degranulation in the heart and inhibiting the activation of a local reninangiotensin system, hence abolishing its detrimental effects on cardiac rhythmicity, appears to be more significant than the loss of histamine-induced cardioprotection. This suggests that therapeutic targets in the treatment of myocardial ischemia, and potentially congestive heart failure and hypertension, should include prevention of mast cell degranulation, mast cell renin inhibition, local ACE inhibition, ANG II antagonism and H3-receptor activation.

Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis

“…Mast cells and histamine release have been implicated in the development of HF [18,20,41]. Our recent research found that H2R activation worsened mitochondrial dysfunction in ischaemic cardiomyocytes and could therefore enhance myocardial apoptosis [3].…”

The novel H 2 S-donor 4-carboxyphenyl isothiocyanate promotes cardioprotective effects against ischemia/reperfusion injury through activation of mitoK ATP channels and reduction of oxidative stress

“…This NE release is reinforced by renin release from mast cells and activation of a local renin-angiotensin cascade [33]. We evaluated possible effects of 4CPI on arrhythmias and release of NE, renin and ␤-hexo in mouse hearts subjected to I/R.…”

Clinically Relevant Doses of Candesartan Inhibit Growth of Prostate Tumor Xenografts In Vivo through Modulation of Tumor Angiogenesis

“…In this context, the observed antiproliferative effects of ARBs are basically a reflection of AT1-mediated signaling in cancer cells. This approach does not take into account the possible role of locally produced AngII, which has been demonstrated to be of major importance in other cell types (Reid et al, 2011;Angeli et al, 2013;Lu et al, 2013). In addition, this approach also ignores the possibility of ARBinduced AngII-independent effects which have been demonstrated in other cell types (Alhusban et al, 2013).…”

“…Another important consideration in investigating the effects of ARBs is the concomitant treatment with exogenous AngII (Uemura et al, 2003;Kosaka et al, 2007;Chen et al, 2013), which only blunted AngII-mediated effects. This paradigm ignores AngII-independent effects of candesartan as well as the role of locally produced AngII, which has been well characterized in a variety of tissues and cell types (Reid et al, 2011;Angeli et al, 2013;Lu et al, 2013). Recently, candesartan was shown to be proangiogenic in cerebral microvascular endothelial cells via activation of the angiotensin II type 2 (AT2) receptor (Alhusban et al, 2013).…”