Cardiac Mast Cell Degranulation Research Articles

Oxytocin Attenuates Sympathetic Innervation with Inhibition of Cardiac Mast Cell Degranulation in Rats after Myocardial Infarction.

Sympathetic hyperinnervation is the leading cause of fatal ventricular arrhythmia (VA) after myocardial infarction (MI). Cardiac mast cells cause arrhythmias directly through degranulation. However, the role and mechanism of mast cell degranulation in sympathetic remodeling remain unknown. We investigated the role of oxytocin (OT) in stabilizing cardiac mast cells and improving sympathetic innervation in rats. MI was induced by coronary artery ligation. Western blotting, immunofluorescence, and toluidine staining of mast cells were performed to determine the expression and location of target protein. Mast cells accumulated significantly in peri-infarcted tissues and were present in a degranulated state. They expressed OT receptor (OTR), and OT infusion reduced the number of degranulated cardiac mast cells post-MI. Sympathetic hyperinnervation was attenuated as assessed by immunofluorescence for tyrosine hydroxylase (TH). Seven days post-MI, the arrhythmia score of programmed electrical stimulation was higher in vehicle-treated rats with MI than in rats treated with OT. An in vitro study showed that OT stabilized mast cells via the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) signaling pathway. Further in vivo studies on OTR-deficient mice showed worsening mast cell degranulation and worsening sympathetic innervation. OT pretreatment inhibited cardiac mast cell degranulation post-MI and prevented sympathetic hyperinnervation, along with mast cell stabilization via the PI3K/Akt pathway. SIGNIFICANCE STATEMENT: This is the first study to elucidate the role and mechanism of oxytocin (OT) in inflammatory-sympathetic communication mediated sympathetic hyperinnervation after myocardial infarction (MI), providing new approaches to prevent fatal arrhythmias.

Dexmedetomidine preconditioning mitigates myocardial ischemia/reperfusion injury via inhibition of mast cell degranulation

The degranulation of cardiac mast cells is associated with occurrence and development of myocardial ischemia/reperfusion (I/R) injury. Dexmedetomidine has a cardioprotective effect from I/R injury. The purpose of this study was to investigate whether dexmedetomidine preconditioning induced cardioprotection is related to suppression of degranulation of cardiac mast cell. Both in vivo and in vitro experimental results revealed that hemodynamic disorder, arrhythmia, infarct size, histopathological score, and mast cell degranulation were dramatically increased in I/R injury groups compared with non-I/R groups, and mastocyte secretagogue compound 48/80 aggravated these damages, but it can be improved by dexmedetomidine preconditioning. Similarly, compound 48/80 increased levels of cardiac troponin I (cTnI) and tryptase, cardiomyocytes apoptosis, and expression of high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), and nuclear factor-kappa B p65 (NF-κB p65) in cardiac tissues induced by I/R injury, but it can be partially decreased by dexmedetomidine pretreatment. Compound 48/80 inhibited proliferation of H9C2(2−1) and RBL-2H3, exacerbated apoptosis of H9C2(2−1), and elevated levels of cTnI and tryptase, while both of which were abolished by dexmedetomidine pretreatment. Our data suggest that dexmedetomidine preconditioning alleviates the degranulation of mast cells and the apoptosis of cardiomyocytes caused by I/R injury, and inhibits the activation of inflammatory related factors HMGB1, TLR4, and NF-κB p65.

Dexmedetomidine Preconditioning Mitigates Myocardial Ischemia/Reperfusion Injury via Inhibition of Mast Cell Degranulation

Background: The degranulation of cardiac mast cells is associated with the occurrence and development of myocardial ischemia/reperfusion (I/R) injury (MIRI). Dexmedetomidine (DEX) has a cardioprotective effect from I/R injury. The present study investigated whether DEX preconditioning-induced cardioprotection was related to suppression of the degranulation of cardiac mast cells. Methods: The ligation of the left anterior descending coronary artery for 30 min of ischemia and 120 min of reperfusion was used to establish a rat MIRI model in vivo. The MIRI Langendorff model in vitro of rat isolated heart was constructed by global ischemia for 30 min and reperfusion for 60 min. The effect of compound 48/80 (C48/80) and DEX pretreatment on MIRI was then evaluated. Hemodynamics and electrocardiogram were assessed for each rat/heart. TTC staining, hematoxylin-eosin staining, and toluidine blue staining, transmission electron microscope detection, TUNEL staining, ELISA, IHE staining, qRT-PCR, and western blot were detected. Further work was performed using a cell coculture test to verify. Findings: In vivo and in vitro experimental results revealed that hemodynamic disorder, arrhythmia, infarct size, histopathological score, and mast cell degranulation were dramatically increased in the I/R injury groups compared to the non-I/R groups. Mastocyte secretagogue compound 48/80 (C48/80) aggravated these damages, and DEX preconditioning mitigated these damages. C48/80 increased the levels of I/R injury-induced cardiac troponin-1 (cTnI) and tryptase, cardiomyocytes apoptosis, and the expression of high mobility group protein B1 (HMGB1), Toll-like receptor 4 (TLR4), and nuclear factor kappa B (NF-κB) p65 in cardiac tissues, and DEX pretreatment partially reduced these changes. C48/80 inhibited the proliferation of H9C2(2-1) and RBL-2H3, exacerbated apoptosis of H9C2(2-1), and increased the levels of cTnI and tryptase, and DEX pretreatment abolished these changes. Interpretation: Our data suggest that DEX preconditioning alleviates the MIRI-induced degranulation of mast cells and the apoptosis of cardiomyocytes, and inhibits the activation of inflammatory-related factors HMGB1, TLR4, and NF-κB p65. Funding Information: This research was supported by the National Natural Science Foundation of China (81860050 & 82060060), Yunnan Health Training Project of High Levels Talents (L-2018007), Program for Innovative Research Team of Kunming Medical University (CXTD201802), Yunnan Provincial Ten Thousand-Talent Program-Famous Doctor (YNWR-MY-2018-043), Innovative fund of Kunming Medical University (2020D013), and Yunnan Provincial Education Department (2020Y0120). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All experimental procedures were performed in accordance with the guidelines formulated by the Institutional Animal Care and Use Committee of Kunming Medical University (No. KMU20191119).

Oxytocin ameliorates ischemia/reperfusion-induced injury by inhibiting mast cell degranulation and inflammation in the rat heart

BackgroundOxytocin (OT) has shown a cardioprotective effect on myocardial ischemia/reperfusion injury (MIRI). This study aimed to investigate whether the cardioprotective effect of OT is associated with the inhibition of mast cell degranulation and inflammation. MethodsThe left anterior descending coronary artery of rats was ligated for 30 min and reperfused for 120 min to establish an ischemia and reperfusion (I/R) injury model. A preliminary experiment was conducted to evaluate the optimal dose of OT (0.01, 0.1, 1 μg/kg via intraperitoneal). The mast cell secretagogue compound 48/80 (C48/80) was used to promote the degranulation of mast cells with or without I/R injury, while rats were pretreated with OT to determine whether this compound suppresses mast cell degranulation. The expression of the inflammatory factors HMGB1 and NF-κB p65 was evaluated. A cell experiment was performed for verification. ResultsC48/80 (0.5 mg/kg, intravenous) increased mast cell degranulation and tryptase release compared with I/R-treated alone (27.12 ± 3.52 % vs. 16.57 ± 2.23 %; 8.34 ± 1.66 ng/mL vs. 3.63 ± 0.63 ng/mL), but these effects could be decreased by OT (0.1 μg/kg, intraperitoneal) preconditioning (19.29 ± 0.74 %; 5.37 ± 0.73 ng/mL). Besides that, hemodynamic disorders, arrhythmias, cardiac edema, infarct size, histopathological damage, and the levels of cTnI, HMGB1 and NF-κB p65 were significantly increased in I/R-treated group compared with corresponding observations in the control group, and C48/80 exacerbated these injuries, but pretreatment with OT could ameliorate these effects. Furthermore, C48/80 (10 μg/mL) inhibited the viability and promoted the apoptosis of H9C2(2-1) and RBL-2H3 cells, and increased the release of cTnI and tryptase, all of which were reversed by prophylactic OT (0.01 ng/mL) treatment. ConclusionWe concluded that OT pretreatment inhibits the degranulation of cardiac mast cells induced by I/R injury and downregulates the expression of the inflammatory factors HMGB1 and NF-κB p65.

Role of cardiac mast cells in exercise training-mediated cardiac remodeling in angiotensin II-infused ovariectomized rats

AimsRegular exercise is recommended in postmenopausal women to prevent the development of heart disease, but mechanism underlying the protection is not completely understood. Many studies have suggested that exercise training notably mediated whole body immune and inflammatory functions. Whether exercise training prevents cardiac dysfunction after deprivation of female sex hormones by inhibiting cardiac immune activation is therefore interesting. Main methodsNine-week treadmill running program was introduced in sham-operated and ovariectomized rats. In addition, chronic angiotensin II infusion was further challenged to activate pathological cardiac remodeling. Cardiac remodeling in associated with the density and degranulation of cardiac mast cells was then evaluated. Key findingsWith exogenous angiotensin II-induced hypertension, cardiac hypertrophy with myocardial fibrosis was shown similarly in both sham-operated controls and ovariectomized rats. Although exercise training did not prevent cardiac hypertrophy, myocardial fibrosis was abolished by exercise. While ovariectomy increased both cardiac mast cell density and degranulation percentage, angiotensin II infusion only enhanced mast cell density. Exercise training could not decrease the density of mast cells, but it did normalize the percentage of degranulation in all groups. Correlation analysis suggested that cardiac mast cell activation is inversely associated with cardiomyocyte hypertrophy due to exercise training but is directly correlated to cardiac hypertrophy by angiotensin II infusion. SignificanceExercise training could attenuate cardiac mast cell hyperactivation induced by either deprivation of female sex hormones or excessive angiotensin II. Additionally, cardiac mast cells could be a solution in the distinction between physiological and pathological hypertrophic development.

Substance P-mediated cardiac mast cell activation: An in vitro study

The neuropeptide substance P can induce degranulation of cardiac mast cells at high concentrations. Herein, we seek to further understand substance P activation of cardiac mast cells in the context of other neuropeptides as well as modulation by non-neuropeptides. This is important given the increasingly recognized role of both cardiac mast cells and substance P in adverse cardiac remodeling. To address this, we isolated cardiac mast cells and compared their response to substance P as well as other members from the tachykinin family of peptides, including neurokinin A and hemokinin-1. We also tested the ability of other factors to manipulate the cardiac mast cell response to substance P. We found that while neurokinin A did not induce cardiac mast cell degranulation, both substance P and hemokinin-1 induced a concentration-dependent release of histamine; the maximal response to hemokinin-1 was greater than to substance P. Neurokinin-1 receptor blockade prevented substance P-induced histamine release, while only partially attenuating hemokinin-1-induced histamine release. The antioxidant N-acetylcysteine attenuated histamine release in response to hemokinin-1 and had no effect on substance P-induced histamine release. Selective PPAR-γ agonists attenuated histamine release in response to substance P. These data indicate that substance P activates cardiac mast cells via the neurokinin-1 receptor, and that the activation response is different to other tachykinins. That the response to substance P is receptor mediated and can be modulated by activation of other receptors (PPAR-γ), argues that substance P activation of cardiac mast cells has potential biological significance.

S1P receptor 1-Mediated Anti-Renin-Angiotensin System Cardioprotection: Pivotal Role of Mast Cell Aldehyde Dehydrogenase Type 2.

In the ischemic-reperfused (I/R) heart, renin-containing mast cells (MC) release enzymatically active renin, activating a local renin-angiotensin system (RAS), causing excessive norepinephrine release and arrhythmic dysfunction. Activation of Gi-receptors on MC and/or ischemic preconditioning (IPC) prevent renin release, thus providing anti-RAS cardioprotection. We questioned whether sphingosine-1-phosphate (S1P), a sphingolipid produced in the I/R heart, might afford anti-RAS cardioprotection by activating Gi-coupled S1P1 receptors (S1P1R) on MC. We report that activation of Gi-coupled S1P1R in cardiac MC confers IPC-like anti-RAS cardioprotection due to S1P1R-mediated inhibition of I/R-induced cardiac MC degranulation and renin release. This results from an initial translocation of protein kinase C subtype-ε and subsequent activation of aldehyde dehydrogenase type 2 (ALDH2), culminating in the elimination of the MC-degranulating effects of acetaldehyde and other toxic species produced during I/R. Inhibition of toxic aldehydes-induced MC-renin release prevents local RAS activation, reduces infarct size, and alleviates arrhythmias. Notably, these cardioprotective effects are lacking in hearts and MC from gene-targeted knock-in mice (ALDH2*2) in which ALDH2 enzymatic activity is maximally reduced. Thus, ALDH2 appears to play a pivotal role in this protective process. Our findings suggest that MC S1P1R 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.

Coronary Ischemia Reperfusion (I/R) Increases Degranulation of Cardiac Mast Cells (CMC) Similarly in Male and Female Rats 8 Weeks After Ischemia

Perimenopausal women have a higher risk of mortality within 2 years of myocardial infarction than similarly aged men despite having less left ventricular dysfunction. Cardiac mast cells (CMC) contribute to inflammation after I/R injury. Recent work suggests that estrogen stimulates mast cell degranulation. We tested whether I/R produced increases in CMC numbers and whether degranulation was more extensive 8 weeks after I/R in male or female rats. The number of stable or degranulating CMCs was determined in regions high in CMC density. Three regions were studied: 1) the ventral epicardial surface at the base of the superior vena cava, 2) the rostral pole of the left atrium and 3) the dorsal surface surrounding the right and left pulmonary veins. Both males (P<0.001) and females (P<0.05) showed reductions in fractional shortening (FS) after I/R compared to controls, while males had lower FS after I/R than females (19.3 ± 2.5 vs. 33.3 ± 3.4%, P<0.01). Left ventricular end‐diastolic diameter was increased after I/R only in males (0.77± 0.08 vs. 0.99 ± 0.04, P<0.01). Numbers of CMCs of either sex was not different 8 weeks after I/R in any region examined. The number of degranulating CMCs and the percent of total CMCs that were degranulating were increased in region 3 after I/R in both sexes (26.8 vs. 77.8% in males, P<0.001; and 25.8 vs. 72.3% in females, P<0.001). The percentage of degranulating CMCs was increased similarly across sex in regions 1 and 2 (45‐59% vs. 23‐29%, P<0.05). The data indicate that CMC degranulation continues 8 weeks after I/R injury in regions rostral to the original ischemia. This effect is similar in male and female rats despite less I/R‐induced left ventricular dysfunction in females.

Oxidative stress-mediated cardiac mast cell degranulation

Pulmonary mast cell degranulation is a well-characterized response to diesel exhaust exposure. A primary constituent of fossil fuel combustion is sulfur dioxide (SO2). SO2 was shown to induce mast cell degranulation in an immortalized cell line secondary to induction of intracellular oxidative stress; however, it is not known whether SO2-induced oxidative stress directly triggers the activation of cardiac mast cells. Accordingly, this study sought to determine whether Na2SO3 induces degranulation of cardiac mast cells, and furthermore whether cardiac mast cell activation may be prevented by inhibition of oxidative stress. To this end, cardiac mast cells were isolated from epicardial surface of the heart and incubated with increasing concentrations of Na2SO3 (0, 0.5, or 5 mM). Antioxidant compounds targeting different mechanisms of free radical generation, including ebselen, diphenyleneiodonium (DPI), or α-tocopherol, were incubated with 5 mM of Na2SO3 in order to determine their efficacy in preventing mast cell degranulation. Na2SO3 induced a significant concentration-dependent histamine release from cardiac mast cells ranging from 8.87% to 18.86%, which was prevented by ebselen. No effect was observed with DPI and α-tocopherol under these conditions. In conclusion, these findings indicate that SO2 is capable of producing cardiac mast cell degranulation in vitro; however, the variable effectiveness of the three antioxidants evaluated is indicative of a multifactorial mechanism mediating SO2-induced cardiac mast cell degranulation. The particular effectiveness of ebselen in preventing mast cell degranulation may be related to its multiple mechanisms of preventing oxidative stress.

Cardiac mast cells accumulation and degranulation contribute to collagen deposition after coronary microembolization

To investigate potential pathophysiological role of cardiac mast cells accumulation and degranulation on the collagen deposition after coronary microembolization (CME). CME was induced in miniswine by selective infusion of 15X10(4) microspheres (diameter, 45 mum) into the left anterior descending artery groups (CME group, n=8). Some CME-induced animals were pretreated with the MC stabilizer tranilast (50 mg/kg, twice daily), beginning 2 weeks before CME and thereafter throughout the experimental period (CME +tranilast group, n=8), while some animals received tranilast without CME (tranilast group, n=8). Eight sham-operated animals without CME served as controls. After 30 days, the total number of MC and degranulating MCs and collagen deposition was assessed by histological and electronic microscopy studies. The numbers of total and degranulating MCs and collagen volume fraction (CVF) at day 30 in CME group were significantly higher than those in controls (P <0.01). Treatment with tranilast significantly reduced the numbers of total and degranulating MCs and CVF at day 30 (all P <0.01). There was a significant positive correlation of the CVF with the number of total MCs (r=0.91, P <0.001) and degranulating MCs (r=0.92, P <0.001) over the CME myocardium. MCs accumulation and degranulating contribute to myocardial fibrosis collagen deposition.

Mast cell degranulation – a mechanism for the anti‐arrhythmic effect of endothelin‐1?

The aim of this study was to investigate whether the previously reported anti-arrhythmic effect of endothelin-1 (ET-1) is mediated by degranulation of cardiac mast cells prior to myocardial ischaemia. Male Sprague-Dawley rats received either ET-1 (1.6 nmolxkg(-1)) in the presence or absence of disodium cromoglycate (DSCG; 20 mgxkg(-1)xh(-1)) prior to coronary artery occlusion (CAO). In separate experiments rats were given compound 48/80 (50 microgxkg(-1)) to compare the effects of ET-1 with those of a known mast cell degranulator. Ischaemia-induced ventricular arrhythmias were detected through continuous monitoring of a lead I electrocardiogram. After 30 min of CAO, the hearts were removed and mast cell degranulation determined by histological analysis. A parallel series of sham groups were performed to determine the direct effects of ET-1 and compound 48/80 on mast cell degranulation in the absence of ischaemia. ET-1 and compound 48/80 both exerted profound anti-arrhythmic effects, significantly reducing the total number of ventricular ectopic beats (P < 0.001) and the incidence of ventricular fibrillation (P < 0.05). These anti-arrhythmic effects were abolished by concomitant DSCG infusion prior to CAO. In sham animals ET-1 and compound 48/80 both induced mast cell degranulation (P < 0.001), an effect which was abolished by DSCG, confirming their ability to induce degranulation of mast cells. These results demonstrate for the first time that when given prior to ischaemia ET-1 mediates its anti-arrhythmic effects, at least in part, via cardiac mast cell degranulation.

Reply to Agkul

chymase prevented fibrosis and maintained left ventricle function after left ventricular repair in a rat chronic myocardial infarction model. Heart failure is a chronic syndrome in which cardiac remodeling plays an important role in the pathogenesis; furthermore, cardiac mast cells may be one of the mainstays of pathologic mechanism according to the current studies [2,3]. Protein kinase C signaling is a relatively new signal transduction pathway of mast cell degradation which currently attracts attention. Palaniyandi and coworkers introduced protein kinase C inhibition to prevent cardiac mast cell degranulation without affecting mast cell density and they performed e V1-2 treatment for rat cardiac mast cell degranulation and decreased myocardial fibrosis [4]. Although Kanemitsu and co-workers underlined that inhibition of fibrosis established by cardiac chymase via transforming growth factor-b, our study also demonstrated that chymase, mediator of mast cell degranulation, related with myocardial fibrosis especially by basic-FGF [2]. These new findings and our previous studies [2—5] demonstrate that chymase-positive mast cells were associated with not only increased fibrosis but degradation of these cells may contribute in decreased cardiac inflammation and remodeling. One of my concerns about this excellent study by Kanemitsu is that he and his colleagues may be performing chronic chymase inhibition with oral medications, when according to previous studies, cardiac mast cells have several mediators as tryptase, 5-lipoxygenase, cytokins, histamin, serglycin, proteoglycans, carboxypeptidase. Chymase, tryptase and carboxypeptidase are also known as mast cell-specific proteases. Recent studies show promising progress of mast cell specific proteases, so how can Kenemitsu help us by reducing fibrosis by only preventing onemast— cell specific protease, instead of directmast cells inhibition?

Modulation of cardiac contractility through endothelin-1 release and myocardial mast cell degranulation

The aim of this study was to outline the consequences of a hypertonic saline-dextran-40 (HSD) infusion-induced peripheral flow stimulus on the ventricular function in closed-chest, pentobarbital-anesthetized dogs. We hypothesized that HSD-induced elevation in endothelin-1 (ET-1) and nitric oxide (NO) release can have a role in myocardial contractile responses; and that cardiac mast cells (MC) degranulation may be involved in this process. The consequences of disodium cromoglycate (a MC stabilizer) or ETR-p1/fl peptide (an endothelin-A receptor antagonist) treatment were evaluated. A 4 ml/kg iv HSD40 infusion significantly increased cardiac index and myocardial contractility, and resulted in a decreased peripheral resistance. The postinfusion period was characterized by significant plasma NO and ET-1 elevations, these hemodynamic and biochemical changes being accompanied by a decreased myocardial ET-1 content, NO synthase activity and enhanced myocardial MC degranulation. Disodium cromoglycate treatment inhibited the HSD40-induced elevations in myocardial contractility and MC degranulation, and similar hemodynamic changes were noted after treatment with ETR-p1/fl peptide, together with a normalized myocardial myocardial ET-1 content, NO synthesis and a significant reduction in MC degranulation. These results indicate that peripheral NO and ET-1 release modulates the cardiac contractility through myocardial ET-A receptor activation and MC degranulation.

Adenosine A2Areceptor activation reduces infarct size in the isolated, perfused mouse heart by inhibiting resident cardiac mast cell degranulation

Mast cells are found in the heart and contribute to reperfusion injury following myocardial ischemia. Since the activation of A2A adenosine receptors (A2AARs) inhibits reperfusion injury, we hypothesized that ATL146e (a selective A2AAR agonist) might protect hearts in part by reducing cardiac mast cell degranulation. Hearts were isolated from five groups of congenic mice: A2AAR+/+ mice, A2AAR(-/-) mice, mast cell-deficient (Kit(W-sh/W-sh)) mice, and chimeric mice prepared by transplanting bone marrow from A2AAR(-/-) or A2AAR+/+ mice to radiation-ablated A2AAR+/+ mice. Six weeks after bone marrow transplantation, cardiac mast cells were repopulated with >90% donor cells. In isolated, perfused hearts subjected to ischemia-reperfusion injury, ATL146e or CGS-21680 (100 nmol/l) decreased infarct size (IS; percent area at risk) from 38 +/- 2% to 24 +/- 2% and 22 +/- 2% in ATL146e- and CGS-21680-treated hearts, respectively (P < 0.05) and significantly reduced mast cell degranulation, measured as tryptase release into reperfusion buffer. These changes were absent in A2AAR(-/-) hearts and in hearts from chimeric mice with A2AAR(-/-) bone marrow. Vehicle-treated Kit(W-sh/W-sh) mice had lower IS (11 +/- 3%) than WT mice, and ATL146e had no significant protective effect (16 +/- 3%). These data suggest that in ex vivo, buffer-perfused hearts, mast cell degranulation contributes to ischemia-reperfusion injury. In addition, our data suggest that A2AAR activation is cardioprotective in the isolated heart, at least in part by attenuating resident mast cell degranulation.

Inhibition of Epsilon Protein Kinase C Attenuates Cardiac Mast Cell Degranulation and Remodeling in Hypertension Induced Heart Failure

Inhibition of Epsilon Protein Kinase C Attenuates Cardiac Mast Cell Degranulation and Remodeling in Hypertension Induced Heart Failure

Relaxin induces mast cell inhibition and reduces ventricular arrhythmias in a swine model of acute myocardial infarction

Resident cardiac mast cells, located mainly around coronary vessels and in the right atrium close to the sinoatrial node, are the main repository of cardiac histamine. Inflammatory activation of cardiac mast cells, as occurs upon acute myocardial infarction, causes the release of histamine and prostanoids. These substances lead to severe tachyarrhythmias, cardiodepressive effects and coronary spasm, thus contributing to myocardial damage and early, lethal outcome. Relaxin, known to inhibit mast cell activation, has been recently validated as a cardiotropic hormone, being produced by the heart and acting on specific heart receptors. In this study, we report on a swine model of heart ischemia/reperfusion, currently used to test cardiotropic drugs, in which human recombinant relaxin (2.5 and 5 μg/kg b.w.), given at reperfusion upon a 30-min ischemia, markedly reduced cardiac injury as compared with the vehicle-treated animals. Evidence is provided that relaxin, at both the assayed doses, causes a clear-cut, significant reduction of plasma histamine, increase in cardiac histamine content and decrease in cardiac mast cell degranulation. This is accompanied by a reduction of oxidative cardiac tissue injury (assessed as tissue malondialdehyde) and of the occurrence of severe ventricular arrhythmias. In conclusion, this study provides further insight into the cardioprotective effects of relaxin, which also involve mast cell inhibition, and confirms the relevance of histamine in the pathophysiology of ischemia-reperfusion-induced cardiac injury and dysfunction. It also offers additional evidence for the potential therapeutic effects of relaxin in animal models of disease involving mast cell activation.

Response of cardiac mast cells to atrial natriuretic peptide

Previously, our laboratory demonstrated that cardiac mast cell degranulation induces adverse ventricular remodeling in response to chronic volume overload. The purpose of this study was to investigate whether atrial natriuretic peptide (ANP), which is known to be elevated in chronic volume overload, causes cardiac mast cell degranulation. Relative to control, ANP induced significant histamine release from peritoneal mast cells, whereas isolated cardiac mast cells were not responsive. Infusion of ANP (225 pg/ml) into blood-perfused isolated rat hearts produced minimal activation of cardiac mast cells, similar to that seen in the control group. ANP also did not increase matrix metalloproteinase-2 activity, reduce collagen volume fraction, or alter diastolic or systolic cardiac function compared with saline-treated controls. In a subsequent study to evaluate the effects of natriuretic peptide receptor antagonism on volume overload-induced ventricular remodeling, anantin was administered to rats with an aortocaval fistula. Comparable increases of myocardial MMP-2 activity in treated and untreated rats with an aortocaval fistula were associated with equivalent decreases in ventricular collagen (P < 0.05 vs. sham-operated controls). Cardiac functional parameters and left ventricular hypertrophy were unaffected by anantin. We conclude that ANP is not a cardiac mast cell secretagogue and is not responsible for the cardiac mast cell-mediated adverse ventricular remodeling in response to volume overload.

Sodium sulfite mediated oxidative stress triggers cardiac mast cell degranulation

Exposure to elevated levels of airborne pollutants causes cardiac mast cell activation. Sulfur dioxide, a derived from fossil fuel combustion, has been shown to induce mast cell degranulation in an immortalized cell line. However, it is not known whether sulfur dioxide induced oxidative stress can directly trigger the activation of cardiac mast cells. This study sought to determine if ionization of sodium sulfite (Na2SO3) can induce degranulation of cardiac mast cells, and whether mast cell activation can be prevented by inhibition of oxidative stress. Cardiac mast cells were isolated from the pericardial sac and incubated with increasing concentrations of Na2SO3. Antioxidant compounds targeting different mechanisms of free radical generation, including ebselen, dyphenyleneiodinium (DPI) and tocopherol, were incubated with Na2SO3 in order to determine their efficacy in preventing mast cell degranulation. Sodium sulfite induced a concentration-dependent histamine release from cardiac mast cells which was prevented by ebselen and attenuated by DPI. In contrast, the histamine release was exacerbated by tocopherol. These findings indicate that sulfur dioxide is capable of causing cardiac mast cell degranulation and the variable effectiveness of the antioxidants evaluated is indicative of a multifactorial mechanism mediating sulfur dioxide induced cardiac mast cell degranulation. EPA grant RD-83195301 (GLB)

The Mast Cell: A Potential Therapeutic Target in Myocardial Infarction

Mast cells are multifunctional effector cells of the immune system, capable of producing a variety of vasoactive mediators, cytokines and growth factors. The presence of resident mast cells in the myocardium has been established; however, their exact role in cardiac pathology remains unclear. The current review presents evidence suggesting the importance of mast cells in the infarcted myocardium. Myocardial ischemia and reperfusion results in degranulation of cardiac mast cells, and release of preformed inflammatory mediators, such as TNF-α and histamine in the ischemic area. Mast cell derived products may modulate endothelial gene expression and mononuclear cell cytokine synthesis. During the proliferative phase of healing, significant mast cell accumulation is noted in areas of fibrosis and myofibroblast proliferation. Stem Cell Factor (SCF), the obligate growth factor for mast cells, is induced in the healing myocardium. Mast cells may have an important role in scar formation through the secretion of growth factors and fibrogenic substances (such as TGF-β, basic FGF, tryptase and VEGF), that may promote collagen deposition and angiogenesis. Understanding the role of the mast cell in myocardial infarction is important in order to design site-specific pharmacological interventions that could mitigate inflammatory injury, without interfering with myocardial healing.

Modulation of cardiac mast cell-mediated extracellular matrix degradation by estrogen

There are fundamental differences between males and females with regard to susceptibility to heart disease. Although numerous animal models of heart failure have demonstrated that premenopausal females are afforded cardioprotection and, therefore, fare better in the face of cardiac disease than their male counterparts, many questions as to how this occurs still exist. Recently, we showed that 1) increased mast cell density is associated with adverse ventricular remodeling and 2) chemically induced mast cell degranulation using compound 48/80 resulted in remarkable changes in matrix metalloproteinase (MMP) activity, cardiac collagen structure, and cardiac diastolic function in normal male rats. With the known gender differences in cardiac disease in mind, we sought to examine the effects of chemically induced cardiac mast cell degranulation in isolated, blood-perfused hearts of intact female rats, ovariectomized female rats, and ovariectomized female rats treated with 17beta-estradiol. In response to mast cell degranulation, no significant differences in cardiac function, MMP-2 activity, or collagen volume fraction were observed between intact female rats and ovariectomized female rats treated with estrogen. In the ovariectomized female group, a significant rightward shift in the left ventricular pressure-volume relation, accompanied by a marked 133% increase in active MMP-2 values over that in the intact female group, was noted after treatment with compound 48/80 (P < or = 0.05), along with a significant reduction in collagen volume fraction below control (0.46 +/- 0.23 vs. 0.73 +/- 0.13%, P < or = 0.05). These findings indicate that estrogen's cardioprotective role can be partially mediated by its effects on cardiac mast cells, MMPs, and the extracellular matrix.