Estrogen regulation of myocardial chymase and chymase effects on cardiac remodeling are unknown. To test the hypothesis that estrogen prevents pressure overload-induced adverse cardiac remodeling by inhibiting mast cell chymase release, transverse aortic constriction or sham surgery was performed in 7-week-old intact and ovariectomized rats. Three days prior to creating the constriction, additional groups of ovariectomized rats began receiving 17β-Estradiol, a chymase inhibitor, or a mast cell stabilizer. Left ventricular function, cardiomyocyte size, collagen volume fraction, mast cell density and degranulation, and myocardial and plasma chymase levels were assessed 18 days post-surgery. Aortic constriction resulted in ventricular hypertrophy in intact and ovariectomized groups while collagen volume fraction was increased only in ovariectomized rats. Chymase protein content was increased by aortic constriction in the intact and ovariectomized groups with the magnitude of the increase being greater in ovariectomized rats. Mast cell density and degranulation, plasma chymase levels and myocardial active transforming growth factor- 1 levels were increased by aortic constriction only in ovariectomized rats. Estrogen replacement markedly attenuated the constriction-increased myocardial chymase, mast cell density and degranulation, plasma chymase and myocardial active transforming growth factor- 1 as well as prevented ventricular hypertrophy and increased collagen volume fraction. Chymostatin attenuated the aortic constriction induced ventricular hypertrophy and collagen volume fraction in the ovariectomized rats similar to that achieved by estrogen replacement. Nedocromil yielded similar effects except for the reduction of chymase content. We conclude that the estrogen-inhibited release of mast cell chymase is responsible for the cardioprotection against transverse aortic constriction-induced adverse cardiac remodeling.
Background Cardiac mast cell (MC) proteases, chymase and tryptase, increase proliferation and collagen synthesis in cultured cardiac fibroblasts. However, the question as to why preventing individually the actions of either protease prevents fibrosis when both are released upon MC activation remains unanswered. Since tryptase has the ability to activate MCs in noncardiac tissues via the protease-activated receptor-2 (PAR-2), there is the possibility that its, in vivo, fibrotic role is due to its ability to induce MC degranulation thereby amplifying the release of chymase. Methods This study sought to delineate the interactions between tryptase and chymase in myocardial remodeling secondary to transverse aortic constriction (TAC) for 5 wks in male Sprague Dawley rats untreated or treated with either the tryptase inhibitor, nafamostat mesilate or MC membrane stabilizing drug, nedocromil (n=6/group). In addition, ventricular slices from 6 rat hearts were incubated with tryptase, tryptase plus nafamostat mesilate or chymostatin for 24 h. Results and Conclusion The results indicate the presence of PAR-2 on MCs and that tryptase inhibition and nedocromil prevented TAC-induced fibrosis and increases in MC density, activation, and chymase release. Tryptase also significantly increased chymase concentration in ventricular tissue culture media, which was prevented by the tryptase inhibitor. Hydroxyproline concentration in culture media was significantly increased with tryptase incubation as compared to the control group and the tryptase group incubated with nafamostat mesilate or chymostatin. We conclude that tryptase contributes to TAC-induced cardiac fibrosis primarily via activation of MCs and the amplified release of chymase.
This research was carried out to investigate the thrombolytic effects of the methanolic extracts of five Bangladeshi plants. Phytochemical metabolites of those plants have been identified to elucidate whether the plant-derived metabolites are linked with the thrombolytic effects. Potential computer aided models were adopted in this study to find out a structure-function correlation between the phytochemical constituents and thrombolytic effects using the secondary metabolites as ligands and tissue plasminogen activator (t-PA) as receptor for the best fit ligand-receptor interaction.
Accumulating evidence indicates that substance P is cardioprotective following ischemia-reperfusion primarily due to its potent coronary vasodilator actions. However, an anti-apoptotic effect of substance P has been observed in tenocytes following ischemia, which involved activation of the AKT pathway. This suggests the possibility that substance P also provides cardioprotection via direct actions to activate AKT in myocardial cells. The purpose of this study was to test the hypothesis that substance P attenuates ischemia-related cell death via direct effects on myocardial cells by activating cell survival pathways. Seven-week-old male Sprague-Dawley rats, anesthetized with intraperitoneal pentobarbital sodium (100 mg/kg), were used. The ability of substance P to prevent cellular damage was assessed following ischemia-reperfusion in an isolated heart preparation and in short-term hypoxia without reperfusion using a left ventricular tissue slice culture preparation. In addition, the NK-1 receptor and AKT involvement was assessed using the NK-1 receptor antagonist L732138 and the AKT inhibitor LY294002. The results indicate that substance P reduced the ischemia-related release of lactate dehydrogenase in both preparations and the degree of apoptosis and necrosis in the hypoxic left ventricular slices, indicating its ability to attenuate cell damage; and induced AKT phosphorylation, with both the AKT inhibitor and NK-1 receptor antagonist preventing the increased phosphorylation of AKT and the ability of substance P to attenuate hypoxic cellular damage. It is concluded that substance P reduces ischemia/hypoxia-induced myocardial cell death by acting directly on cardiac cells to initiate cell survival pathways via the NK-1 receptor and AKT.
Purpose Ischemia/reperfusion results in tissue damage, a rapid increase in cytokines and chemokines and inflammatory cell infiltration. Herein we investigated the ability of a selective TLR2/4 antagonist, Sparstolonin B (SsnB), to protect rat cultured left ventricular tissue (LV) slices from hypoxic injury by inhibiting the myocardial inflammatory response independent of inflammatory cell infiltration. Methods and Results Media Lactate dehydrogenase (LDH) levels were measured to reflect hypoxia-induced cytotoxicity and cell injury with and without SsnB. Incubation with SsnB (15 and 30 μM) significantly reduced by 20 and 40 %, respectively, the amount of LDH released from the hypoxic LV slices. TUNEL staining showed that SsnB significantly attenuated the levels of hypoxia-induced apoptotic cells from 61.5 ±4.0 to 27.0±2.1 (15 μM SsnB) and 23.5±2.2 (30 μM SsnB) cells/unit area. Similarly, the Periodic Acid-Schiff (PAS) staining of ischemic areas in untreated hypoxic LV slices was increased 17 fold from 0.26±0.09 to 4.41±0.43 %, while in hypoxic slices incubated with 15 and 30 μM of SsnB, the PAS positive ischemic areas were increased by only 6.4 fold to 1.66±0.39 % and 3.8 fold to 1.00±0.22 %, respectively. Rt-PCR confirmed that MCP1 and IL-6 expression during hypoxia was elevated by 2 and 4 fold, respectively, while their upregulation was significantly inhibited (i.e., <0.7 fold increase) by SsnB. Conclusion The selective TLR2/4 antagonist, Sparstolonin B, can substantially protect LV myocardium via its ability to inhibit injury resulting from hypoxic myocardial-generated inflammation. Accordingly SsnB has potential as a therapeutic agent for the attenuation of myocardial ischemia-reperfusion injury.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.