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.     

Prevention of adverse cardiac remodeling to volume overload in female rats is the result of an estrogen-altered mast cell phenotype

Previously, we have reported sex differences in the cardiac remodeling response to ventricular volume overload whereby male and ovariectomized (OVX) female rats develop eccentric hypertrophy, and intact (Int) female rats develop concentric hypertrophy. In males, this adverse remodeling has been attributed to an initial cascade of events involving myocardial mast cell and matrix metalloproteinase activation and extracellular collagen matrix degradation. The objective of this study was to determine the effect of female hormones on this initial cascade. Accordingly, an aortocaval fistula (Fist) was created in 7-wk-old Int and OVX rats, which, together with sham-operated (sham) controls, were studied at 1, 3, and 5 days postsurgery. In Int-Fist rats, myocardial mast cell density, collagen volume fraction, endothelin (ET)-1, stem cell factor (SCF), and TNF-α remained at control levels or were minimally elevated throughout the study period. This was not the case in the OVX-Fist group, where the initial response included significant increases in mast cell density, collagen degradation, ET-1, SCF, and TNF-α. These events in the OVX-Fist group were abolished by prefistula treatment with a mast cell stabilizer nedocromil. Of note was the observation that ET-1, TNF-α, SCF, and collagen volume fraction values for the OVX-sham group were greater than those of the Int-sham group, suggesting that the reduction of female hormones alone results in major myocardial changes. We concluded that female hormone-related cardioprotection to the volume stressed myocardium is the result of an altered mast cell phenotype and/or the prevention of mast cell activation.     

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

The objective of this study was to investigate the effect a nonselective endothelin-1 (ET-1) receptor antagonist (bosentan) had on the acute myocardial remodeling process including left ventricular (LV) mast cells and matrix metalloproteinase (MMP) activity secondary to volume overload. Additionally, we investigated the overall functional outcome of preventative endothelin receptor antagonism during 14 days of chronic volume overload. LV tissue from sham-operated (Sham), untreated-fistula (Fist), and bosentan (100 mg.kg(-1).day(-1))-treated animals (Fist + Bos) was analyzed for mast cell density, MMP activity, and myocardial collagen volume fraction at 1 and 5 days after the creation of an aortocaval fistula. When compared with untreated fistulas, bosentan treatment prevented the marked increase in LV mast cell density at 1 day postfistula (3.1 +/- 0.3 vs. 1.3 +/- 0.3 LV mast cells/mm2, Fist vs. Fist + Bos, P 相似文献   

心房钠尿肽通过上调OPA1表达抑制心衰小鼠心肌线粒体分裂并改善心脏功能

目的:探讨心房钠尿肽(Atrial natriuretic peptide,ANP)对后负荷增加引起的心脏功能下降的保护作用及其机制。方法:选择雄性C57小鼠30只,将其随机分为假手术组(sham)、主动脉弓结扎(Transverse aortic constriction,TAC)手术组和主动脉弓结扎手术ANP干预组(TAC+ANP)。ANP通过皮下注射4周,随后超声检测心脏功能、四腔心切片观察心肌重构,电镜观察心肌线粒体的形态与数量,Western-Blot检测心肌组织中融合分裂相关分子的表达。结果:同sham组相比,TAC组射血分数(Ejection fraction,EF)降低,且左室舒张末内径(End-diastolic left ventricular internal diameter,LVIDd)、左室舒张期后壁厚度(End-diastolic left ventricular posterior wall thickness,LVPWd)、左室质量(LV mass)、心肌质量/胫骨长度(Heart weight/tibial length,HW/TL)显著增加(P0.05),线粒体面积减小伴数量增加(P0.05),且线粒体融合相关蛋白OPA1表达量下降(P0.05)。同TAC组相比,TAC+ANP组EF显著增加,且LVIDd、LV mass、HW/TL均显著下降(P0.05),线粒体面积增加伴数量减少(P0.05),且线粒体融合相关蛋白OPA1表达量上调(P0.05)。在离体培养的心肌细胞中,给予ANP处理可减轻H_2O_2诱导的OPA1表达下降,给与ANP竞争性多肽抑制剂anantin后该作用消失。结论:ANP通过上调OPA1的表达抑制线粒体分裂改善后负荷增加导致的心脏功能下降。     

Cardioprotection in female rats subjected to chronic volume overload: synergistic interaction of estrogen and phytoestrogens

Intact female rats fed a high-phytoestrogen diet are protected against adverse left ventricular (LV) remodeling induced by chronic volume overload. We hypothesized that both phytoestrogens and ovarian hormones, particularly estrogen, are necessary for this dietary-induced cardioprotection. To test this hypothesis, eight groups of female rats were studied; rats were fed either a high-phytoestrogen (+phyto) or phytoestrogen-free diet. Groups included sham-operated rats, intact rats with fistula (Fist), ovariectomized rats with fistula (Fist-OX), and Fist-OX rats treated with estrogen (EST). Myocardial function and remodeling were assessed after 8 wk of volume overload using a blood-perfused isolated heart apparatus. Fist-OX rats developed significant ventricular dilatation and increased compliance vs. intact Fist rats, which were associated with a significant decrease in contractility. Estrogen treatment prevented pulmonary edema and attenuated LV hypertrophy and dilatation but did not maintain contractility. However, dietary phytoestrogens completely prevented LV dilatation in both the Fist+phyto and Fist-OX+EST+phyto groups but had no effect on LV remodeling in the Fist-OX+phyto group. Contractility was significantly greater in the estrogen-treated rats fed the phytoestrogen diet than in those treated with estrogen alone. Dietary phytoestrogens did not affect LV or uterine mass, serum estrogen, LV estrogen receptor expression, or cardiac function in sham animals. These data indicate that estrogen is not solely responsible for the cardioprotection exhibited by intact females and that phytoestrogens can work synergistically with ovarian hormones to attenuate ventricular remodeling induced by chronic volume overload in female rats.     

The presence of ANP in rat peritoneal mast cells

Atrial natriuretic peptide （ANP） is an important component of the natriuretic peptide system. A great role in many regulatory systems is played by mast cells. Meanwhile involvement of these cells in ANP activity is poorly studied. In this work, we have shown the presence of ANP in rat peritoneal mast cells. Pure fraction of mast cells was obtained by separation of rat peritoneal cells on a Percoll density gradient. By Westem blotting, two ANP-immunoreactive proteins of molecular masses of 2.5 kDa and 16.9 kDa were detected in lysates from these mast cells. Electron microscope immunogold labeling has revealed the presence of ANP-immunoreactive material in storage, secreting and released granules of mast cells. Our findings indicate the rat peritoneal mast cells to contain both ANP prohormone and ANP. These both peptides are located in mast cell secretory granules and released by mechanism of degranulation. It is discussed that many mast cell functions might be due to production of natriuretic peptides by these cells.     

Endothelin-1 mediates cardiac mast cell degranulation, matrix metalloproteinase activation, and myocardial remodeling in rats

The objective of this study was to determine whether elevated circulating levels of endothelin (ET)-1 are capable of mediating left ventricular (LV) mast cell degranulation and thereby induce matrix metalloproteinase (MMP) activation. After the administration of 20 pg/ml ET-1 to blood-perfused isolated rat hearts, LV tissue was analyzed for signs of mast cell degranulation and MMP activation. Relative to control, ET-1 produced extensive mast cell degranulation as well as a significant increase in myocardial water content (78.8 +/- 1.5% vs. 74.2 +/- 2.2%, P <0.01), a marked 107% increase in MMP-2 activity (P <0.05), and a substantial decrease in collagen volume fraction (0.69 +/- 0.09% vs. 0.99 +/- 0.04%, P <0.001). Although the myocardial edema would be expected to increase ventricular stiffness, compliance was not altered, and moderate ventricular dilatation was observed (end-diastolic volume at end-diastolic pressure of 0 mmHg of 330.2 +/- 22.1 vs. 298.9 +/- 17.4 microl in ET-1 treated vs. control, respectively, P=0.07). Additionally, pretreatment with the mast cell stabilizer nedocromil prevented ET-1-induced changes in MMP-2 activity, myocardial water content, collagen volume fraction, and end-diastolic volume. These findings demonstrate that ET-1 is a potent cardiac mast cell secretogogue and further indicate that ET-1-mediated mast cell degranulation is a potential mechanism responsible for myocardial remodeling.     

Chronic all-trans retinoic acid treatment prevents medial thickening of intramyocardial and intrarenal arteries in spontaneously hypertensive rats

There are in vitro data linking all-trans retinoic acid (atRA) with inhibition of hypertrophy and hyperplasia in cardiomyocytes, vascular smooth muscle cells, and fibroblasts. In the present study, we tested the hypothesis that chronic treatment with atRA may blunt the process of myocardial remodeling in spontaneously hypertensive rats (SHR). Four-week-old male SHR were treated with atRA (5 or 10 mg.kg-1.day-1) given daily for 3 mo by gavage; age- and sex-matched Wistar-Kyoto rats (WKY) and placebo-treated SHR served as controls. At the end of the treatment period, cardiac geometry and function were assessed by Doppler echocardiography. Histological examination and RIA were performed to evaluate medial thickening of intramyocardial and renal arteries, perivascular and interstitial collagen content, and atrial natriuretic peptide (ANP) and IGF-I in the heart, respectively. The novel finding of the present study is that atRA prevented hypertrophy of intramyocardial and intrarenal arteries and ventricular fibrosis. However, atRA treatment did not lower blood pressure or left ventricular weight and left ventricular weight-to-body weight ratio in SHR. atRA did not change cardiac geometry and function as assessed by Doppler echocardiography. atRA showed no influence on either ANP or IGF-I levels. In conclusion, the present study suggests that chronic atRA treatment prevents medial thickening of intramyocardial and intrarenal arteries and ventricular fibrosis during the development of hypertension. Left ventricular hypertrophy and cardiac geometry and function are not changed by atRA treatment.     

The role of mast cells in atrial natriuretic peptide-induced cutaneous inflammation

Atrial natriuretic peptide (ANP) is widely distributed throughout the heart, skin, gastrointestinal and genital tracts, and nervous and immune systems. ANP acts to mediate vasodilation and induces mast cell activation in both human and rats in vitro. However, the mechanisms of ANP-induced mast cell activation, the extent to which ANP can induce tissue swelling, mast cell degranulation, and granulocyte infiltration in mouse skin are not fully understood. This issue was investigated by treatment with ANP in rat peritoneal mast cells (RPMCs) and mouse peritoneal mast cells (MPMCs) in vitro and by injection of ANP into the skin of congenic normal WBB6F1/J-Kit+/Kit+ +/+, genetically mast cell-deficient WBB6F1/J-Kit(W)/Kit(W-v) (W/W(v)) and mast cell-engrafted W/W(v) (BMCMC→W/W(v)) mice in vivo. ANP induced the release of histamine and TNF-α from RPMCs and enhanced serotonin release from MPMCs, in a dose-dependent fashion, as well as reduced cAMP level of RPMCs in vitro. In +/+ mice, ANP induced significant tissue swelling, mast cell degranulation, and granulocyte infiltration in a dose-dependent manner, whereas not in genetically mast cell-deficient W/W(v) mice. However, ANP-induced cutaneous inflammation has been restored in BMCMC→W/W(v) mice. These data indicate that mast cells play a key role in the ANP-induced cutaneous inflammation.     

Brain natriuretic peptide appears to act locally as an antifibrotic factor in the heart

In addition to cardiac myocyte hypertrophy, proliferation and increased extracellular matrix production of cardiac fibroblasts occur in response to cardiac overload. This remodeling of the cardiac interstitium is a major determinant of pathologic hypertrophy leading to ventricular dysfunction and heart failure. Atrial and brain natriuretic peptides (ANP and BNP) are cardiac hormones produced primarily by the atrium and ventricle, respectively. Plasma ANP and BNP concentrations are elevated in patients with hypertension, cardiac hypertrophy, and acute myocardial infarction, suggesting their pathophysiologic roles in these disorders. ANP and BNP exhibit diuretic, natriuretic, and vasodilatory activities via a guanylyl cyclase-coupled natriuretic peptide receptor subtype (guanylyl cyclase-A or GC-A). Here we report the generation of mice with targeted disruption of BNP (BNP-/- mice). We observed focal fibrotic lesions in ventricles from BNP-/- mice with a remarkable increase in ventricular mRNA expression of ANP, angiotensin converting enzyme (ACE), transforming growth factor (TGF)-beta3, and pro-alpha1(I) collagen [Col alpha1(I)], which are implicated in the generation and progression of ventricular fibrosis. Electron microscopic examination revealed supercontraction of sarcomeres and disorganized myofibrils in some ventricular myocytes from BNP-/- mice. No signs of cardiac hypertrophy and systemic hypertension were noted in BNP-/- mice. In response to acute cardiac pressure overload induced by aortic constriction, massive fibrotic lesions were found in all the BNP-/- mice examined, accompanied by further increase of mRNA expression of TGF-beta3 and Col alpha1(I). We postulate that BNP acts as a cardiocyte-derived antifibrotic factor in the ventricle.     

Gender mediated cardiac protection from adverse ventricular remodeling is abolished by ovariectomy

Gender differences in the prevalence of cardiovascular disease have been observed both clinically and experimentally. These cardioprotective effects have frequently been attributed to female hormones, however, the underlying mechanisms responsible for this cardioprotection are still poorly understood. Accordingly, this study sought to determine the contribution of ovarian hormones to the prevention of adverse ventricular remodeling and congestive heart failure in chronic volume overload (i.e. aortocaval fistula in intact or ovariectomized female rats). Ovariectomized rats developed more extensive cardiac remodeling than intact females at 21 weeks post-fistula, characterized by significantly greater left ventricular (LV) hypertrophy (167 vs. 86%, respectively, p < 0.05) and a substantial increase in LV dilatation (71%, p < 0.05) relative to control. In contrast to the eccentric hypertrophy in ovariectomized females post-fistula, the hypertrophic response in the intact female hearts was essentially concentric. While neither fistula group suffered significant mortality, there was a marked increase in the lung weight of ovariectomized rats (87%, p < 0.05) consistent with the development of pulmonary edema. Overall, the extent of myocardial remodeling and decrease in LV function in the ovariectomized females was comparable to those changes reported for males with symptomatic heart failure, while intact females maintained chronic compensated ventricular function similar to that of controls. The marked ventricular dilatation and symptoms of congestive heart failure seen at 21 weeks post-fistula in the ovariectomized females clearly demonstrate the influence of circulating ovarian hormones on the pattern of myocardial remodeling resulting from a chronic volume overload.     

Attenuated diuretic and natriuretic effects of atrial natriuretic peptide in rats with heart failure

Plasma levels of atrial natriuretic peptide (ANP) and renal responses to ANP were examined in rats with chronic cardiac failure produced by coronary artery ligation and in sham-operated controls. Plasma ANP levels were elevated in the rats with severe cardiac failure as compared with the controls (P less than 0.001). ANP injections at the doses of 1, 5, 25 and 50 micrograms/kg increased water and sodium excretion significantly at all but the lowest dose in the controls; only the two largest doses caused clear diuresis and natriuresis in the heart failure group. The diuretic and natriuretic effects of ANP were significantly weaker at the doses of 5 and 25 micrograms/kg in the rats with heart failure as compared with the controls. We conclude, that natriuretic and diuretic effects of ANP are attenuated in this chronic heart failure mode.     

Cardiac mast cell-mediated activation of gelatinase and alteration of ventricular diastolic function

Mast cells contain proteases capable of activating matrix metalloproteinases (MMPs). However, given the relatively low density of mast cells in the myocardium (i.e., 1.5-5.3 cells/mm(2)), it is unknown whether these enzymes are present in sufficient quantities in the normal heart to mediate MMP activation. Accordingly, this study sought to determine whether chemically induced degranulation of cardiac mast cells (with compound 48/80) would have an effect in isolated, blood-perfused, functioning rat hearts. Mast cell degranulation produced a 15% increase in histamine levels present in the coronary efflux, a significant increase in myocardial water (i.e., edema) relative to normal values (80.1 +/- 3.4% vs. 77.4 +/- 1.08%, P < or = 0.03), a substantial activation of MMP-2 (126% increase relative to controls, P < or = 0.02), and a marked decrease in myocardial collagen volume fraction (0.46 +/- 0.10% vs. 0.97 +/- 0.33%, P < or = 0.001). Furthermore, although an increase in ventricular stiffness was expected due to the extent of edema resulting from mast cell degranulation, modest ventricular dilatation was observed. These findings clearly demonstrate that the number of mast cells present in normal hearts is sufficient to mediate activation of MMPs and produce extracellular matrix degradation, thereby potentially causing subsequent ventricular dilatation.     

Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy

Alteration of hemodynamic loading induces remodeling that includes changes in myocardial properties and extracellular matrix structure. We investigated the hypothesis that cardiac hypertrophy due to volume overload produces changes in myocardial diastolic mechanics and stiffness that are in part due to alterations in advanced glycation end-product (AGE) collagen cross-linking. Rats developed volume overload induced by arteriovenous fistula (AVF). To assess the dependence of AGE cross-linking on mechanics, we prevented AGE formation by administering the drug aminoguanidine (AG) to one group of AVF rats (AG+AVF). Volume overload did not modify collagen concentration. Right ventricular AGE cross-links were modestly elevated in AVF hearts but were significantly reduced by AG. AVF rats exhibited significantly increased septal AGE cross-links that were inhibited in the AG+AVF group. AVF-induced increases in left ventricular longitudinal stiffness and septal circumferential stiffness were prevented in AG+AVF hearts. Volume overload appears to regionally modify AGE collagen cross-linking and stiffness, and AG treatment prevented these increases, demonstrating that AGE cross-linking plays a role in mediating diastolic compliance in volume-overload hypertrophy.     

Increased natriuretic peptide receptor A and C gene expression in rats with pressure-overload cardiac hypertrophy

Both atrial (ANP) and brain (BNP) natriuretic peptide affect development of cardiac hypertrophy and fibrosis via binding to natriuretic peptide receptor (NPR)-A in the heart. A putative clearance receptor, NPR-C, is believed to regulate cardiac levels of ANP and BNP. The renin-angiotensin system also affects cardiac hypertrophy and fibrosis. In this study we examined the expression of genes for the NPRs in rats with pressure-overload cardiac hypertrophy. The ANG II type 1 receptor was blocked with losartan (10 mg.kg(-1).day(-1)) to investigate a possible role of the renin-angiotensin system in regulation of natriuretic peptide and NPR gene expression. The ascending aorta was banded in 84 rats during Hypnorm/Dormicum-isoflurane anesthesia; after 4 wk the rats were randomized to treatment with losartan or placebo. The left ventricle of the heart was removed 1, 2, or 4 wk later. Aortic banding increased left ventricular expression of NPR-A and NPR-C mRNA by 110% (P < 0.001) and 520% (P < 0.01), respectively, after 8 wk; as expected, it also increased the expression of ANP and BNP mRNAs. Losartan induced a slight reduction of left ventricular weight but did not affect the expression of mRNAs for the natriuretic peptides or their receptors. Although increased gene expression does not necessarily convey a higher concentration of the protein, the data suggest that pressure overload is accompanied by upregulation of not only ANP and BNP but also their receptors NPR-A and NPR-C in the left ventricle.     

Atrial natriuretic peptide-dependent modulation of hypoxia-induced pulmonary vascular remodeling

Hypoxic stress upsets the balance in the normal relationships between mitogenic and growth inhibiting pathways in lung, resulting in pulmonary vascular remodeling characterized by hyperplasia of pulmonary arterial smooth muscle cells (PASMCs) and fibroblasts and enhanced deposition of extracellular matrix. Atrial natriuretic peptide (ANP) reduces pulmonary vascular resistance and attenuates hypoxia-induced pulmonary hypertension in vivo and PASMC proliferation and collagen synthesis in vitro. The current study utilized an ANP null mouse model (Nppa-/-) to test the hypothesis that ANP modulates the pulmonary vascular and alveolar remodeling response to normobaric hypoxic stress. Nine-10 wk old male ANP null (Nppa-/-) and wild type nontransgenic (NTG) mice were exposed to chronic hypoxia (10% O(2), 1 atm) or air for 6 wks. Measurement: pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial and alveolar remodeling were assessed. Hypoxia-induced pulmonary arterial hypertrophy and muscularization were significantly increased in Nppa-/- mice compared to NTG controls. Furthermore, the stimulatory effects of hypoxia on alveolar myofibroblast transformation (8.2 and 5.4 fold increases in Nppa-/- and NTG mice, respectively) and expression of extracellular matrix molecule (including osteopontin [OPN] and periostin [PN]) mRNA in whole lung were exaggerated in Nppa-/- mice compared to NTG controls. Combined with our previous finding that ANP signaling attenuates transforming growth factor (TGF)-beta-induced expression of OPN and PN in isolated PASMCs, the current study supports the hypothesis that endogenous ANP plays an important anti-fibrogenic role in the pulmonary vascular adaptation to chronic hypoxia.     

Cardiac-specific attenuation of natriuretic peptide A receptor activity accentuates adverse cardiac remodeling and mortality in response to pressure overload

Atrial (ANP) and brain (BNP) natriuretic peptides are hormones of myocardial cell origin. These hormones bind to the natriuretic peptide A receptor (NPRA) throughout the body, stimulating cGMP production and playing a key role in blood pressure control. Because NPRA receptors are present on cardiomyocytes, we hypothesized that natriuretic peptides may have direct autocrine or paracrine effects on cardiomyocytes or adjacent cardiac cells. Because both natriuretic peptides and NPRA gene expression are upregulated in states of pressure overload, we speculated that the effects of the natriuretic peptides on cardiac structure and function would be most apparent after pressure overload. To attenuate cardiomyocyte NPRA activity, transgenic mice with cardiac specific expression of a dominant-negative (DN-NPRA) mutation (HCAT D 893A) in the NPRA receptor were created. Cardiac structure and function were assessed (avertin anesthesia) in the absence and presence of pressure overload produced by suprarenal aortic banding. In the absence of pressure overload, basal and BNP-stimulated guanylyl cyclase activity assessed in cardiac membrane fractions was reduced. However, systolic blood pressure, myocardial cGMP, log plasma ANP levels, and ventricular structure and function were similar in wild-type (WT-NPRA) and DN-NPRA mice. In the presence of pressure overload, myocardial cGMP levels were reduced, and ventricular hypertrophy, fibrosis, filling pressures, and mortality were increased in DN-NPRA compared with WT-NPRA mice. In addition to their hormonal effects, endogenous natriuretic peptides exert physiologically relevant autocrine and paracrine effects via cardiomyocyte NPRA receptors to modulate cardiac hypertrophy and fibrosis in response to pressure overload.     

Effects of dietary phytoestrogens on cardiac remodeling secondary to chronic volume overload in female rats.

Previously, we demonstrated that intact female rats fed a standard rodent diet containing soybean products exhibit essentially no adverse left ventricular (LV) remodeling in response to aortocaval fistula-induced chronic volume overload. We hypothesized that phytoestrogenic compounds in the diet contributed to the female cardioprotection. To test this hypothesis, four groups of female rats were studied: sham-operated (Sham) and fistula (Fist) rats fed a diet with [P(+)] or without [P(-)] phytoestrogens. Eight weeks postfistula, systolic and diastolic cardiac function was assessed by using a blood-perfused, isolated heart preparation. High-phytoestrogen diet had no effect on body, heart, and lung weights, or cardiac function in Sham rats. Fistula groups developed LV hypertrophy, which was not reduced by dietary phytoestrogens [1,184 +/- 229 mg Fist-P(-) and 1,079 +/- 199 mg Fist-P(+) vs. 620 +/- 47 mg for combined Sham groups, P < 0.05]. Unstressed LV volume increased in Fist-P(-) rats (428 +/- 16 vs. 300 +/- 14 microl Sham, P < 0.0001), but it was not different from Sham for Fist-P(+) animals (286 +/- 17 microl). Fist-P(-) rats developed increased ventricular compliance (5.3 +/- 0.8 vs. 2.3 +/- 0.3 microl/mmHg Sham, P < 0.01), whereas Fist-P(+) rats had no change in compliance (2.8 +/- 0.4 mul/mmHg). Intrinsic ventricular contractility was maintained in the Fist-P(+) rats, but it was reduced (P < 0.001) in the Fist-P(-) rats [systolic pressure-volume slope: 1.04 +/- 0.03, 0.60 +/- 0.06, and 0.99 +/- 0.08 mmHg/microl, for Fist-P(+), Fist-P(-), and Sham, respectively]. These data indicate that dietary phytoestrogens contribute significantly to female cardioprotection against volume overload-induced adverse ventricular remodeling and that studies evaluating gender differences in cardiovascular remodeling must consider the influence of dietary phytoestrogens.     

Protective role of mast cells in homocysteine-induced cardiac remodeling

Recent reports including those from our laboratories indicate that hyperhomocysteinemia (Hhe) is an independent risk factor for cardiac dysfunction and clinical heart failure. Mast cell accumulation is a prominent feature in our model of Hhe-induced cardiac dysfunction. Because mast cell-derived mediators can potentially attenuate cardiac remodeling, we investigated the possible protective role of mast cells in Hhe-induced cardiac remodeling using a mast cell-deficient rat model that in our recent report did not demonstrate any adverse cardiac function at younger age (6 mo) than mast cell-competent control animals. Mast cell-deficient (Ws/Ws) rats and mast cell-competent (+/+) littermate control animals (3 mo of age) were treated with a Hhe-inducing diet for 10 wk. Cardiac remodeling was assessed structurally utilizing histomorphometric methods and functionally using an isolated Langendorff-perfused heart preparation. The Hhe-inducing diet caused similar elevations of homocysteine levels in the two groups. Compared with Hhe +/+ rats, the Hhe Ws/Ws rats demonstrated strikingly exacerbated adverse cardiac remodeling and myocardial fibrosis. Cardiac function measurement showed worsened diastolic function in Hhe Ws/Ws rats compared with Hhe +/+ rats. The absence of mast cells strikingly exacerbates Hhe-induced adverse cardiac remodeling and diastolic dysfunction. These findings indicate a potential dual rather than sole deleterious role for mast cells in cardiac injury.     

Histochemical study of cardiac mast cells degranulation and collagen deposition: interaction with the cathecolaminergic system in the rat

Although their role in the cardiovascular system is still largely unknown, mast cells are present in the myocardium of both experimental animals and humans. Interestingly, cathecolaminergic nerve fibres and mast cells are often described in close morphological and functional interactions in various organs. In the present study we investigated the effects of chronic interference with beta-adrenergic receptors (via either sympathectomy or beta-blockade) on cardiac mast cell morphology/activation and on interstitial collagen deposition. In rats subjected to chemical sympathectomizy with the neurotoxin 6-hydroxydopamine (6-OHDA) we observed a significant increase of mast cell density, and in particular of degranulating mast cells, suggesting a close relationship between the cardiac catecholaminergic system and mast cell activation. In parallel, chronic 6-OHDA treatment was associated with increased collagen deposition. The influence of the beta-adrenergic receptor component was investigated in rats subjected to chronic propranolol administration, that caused a further significant increase in mast cell activation associated with a lower extent of collagen deposition when compared to chemical sympathectomy. These data are the first demonstration of a close relationship between rat cardiac mast cell activation and the catecholaminergic system, with a complex interplay with cardiac collagen deposition. Specifically, abrogation of the cardiac sympathetic efferent drive by chemical sympathectomy causes mast cell activation and interstitial fibrosis, possibly due to the local effects of the neurotoxin 6-hydroxydopamine. In contrast, beta-adrenergic blockade is associated with enhanced mast cell degranulation and a lower extent of collagen deposition in the normal myocardium. In conclusion, cardiac mast cell activation is influenced by beta-adrenergic influences.