Scholarly article on topic 'Sympathetic endothelin A receptors contribute to the development of heart failure'

Sympathetic endothelin A receptors contribute to the development of heart failure Academic research paper on "Basic medicine"

CC BY-NC-ND
0
0
Share paper
Academic journal
Life Sciences
OECD Field of science
Keywords
{}

Academic research paper on topic "Sympathetic endothelin A receptors contribute to the development of heart failure"

e56

Abstracts

ET-1, promoted the pathophysiological phenotypes of HCM in the iPSC-derived cardiomyocytes.

doi:10.1016/j.lfs.2013.12.188

Endothelin receptor antagonists exacerbate autoimmune myocarditis in mice

Kazuko Tajiriab, Satoshi Sakaiab, Taizo Kimuraab, Tomoko Machino-Ohtsukaab, Zheng Wanga b, Akira Satoa b, Takashi Miyauchib, Kazutaka Aonumaa,b

aCardiovascular Division, Faculty of Medicine, University ofTsukuba,

Tsukuba, Ibaraki, Japan

bDepartment of Pathology and Matrix Biology,

Mie University Graduate School of Medicine, Tsu, Mie, Japan

E-mail address: ktajiri@md.tsukuba.ac.jp (K. Tajiri)

Background: Experimental autoimmune myocarditis (EAM) is a mouse model of inflammatory cardiomyopathy. The amount of endothelin (ET) increases according to the disease progression; however, the pathological role of ET in myocarditis has not been elucidated. Methods and results: EAM was induced by immunization of cardiac myosin peptide with complete Freund's adjuvant on days 0 and 7 in BALB/c mice. ET-A/-B dual receptor antagonist SB209670 was administered by continuous infusion from a subcutaneous pump for 3 weeks. An increase in heart-to-body weight ratio was observed in SB209670-treated mice compared with vehicle-treated mice. The heart pathology in SB209670-treated mice was remarkable for gross inflammatory infiltration, in contrast to the smaller inflammation in the hearts of vehicle-treated mice. We found that ET blockade decreased the number of Foxp3 + regulatory T cells and inhibited the production of immunoregulatory cytokine 1L-10 in the heart. ET blockade also inhibited the expression of suppressor of cytokine signaling 3 (SOCS3) that plays a key role in the negative regulation of both Toll-like receptor (TLR)- and cytokine receptor-mediated signaling. EAM is a CD4+ T cell-mediated disease. CD4+ T cells isolated from SB209670-treated EAM mice produced less 1L-10 and more inflammatory cytokines IFN-y and 1L-17 than those isolated from vehicle-treated mice. Conclusions: ET receptor antagonist exacerbated autoimmune myocarditis in mice. ET may play an important role in the regulation of inflammation in myocarditis.

doi:10.1016/j.lfs.2013.12.189

Imaging of the binding of ET-1 and of linear ET-1 in rat mesenteric resistance arteries

Dimitrios Kapsokalyvasab, Paul M.H. Schiffersc, Nathan Maijc, Tilman M. Hackengd, Dennis P. Suylend, Marrc A.M.J. van Zandvoorta e, Jo G.R. De Meyc f

aMolecular Cell Biology, Department of Genetics & Cell Biology, Maastricht University, Maastricht, The Netherlands bInstitute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany

cDepartment of Pharmacology, Cardiovascular Research institute Maastricht (CARiM), Maastricht University, Maastricht, The Netherlands dDepartment of Biochemistry, Cardiovascular Research institute Maastricht (CARiM), Maastricht University, Maastricht, The Netherlands einstitute for Molecular Cardiovascular Research (iMCAR), RWTH Aachen University, Aachen, Germany institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

E-mail address: dikapso@yahoo.com (D. Kapsokalyvas)

In engineered cells, endothelin ETA- and ETB-receptors can heterodimerize. We tested whether this is possible in native tissue. Therefore, rat mesenteric resistance arteries were maintained in organ culture for 24 h to upregulate ETB-mediated contractions in addition to their normal ETA-mediated constrictions. Thereafter the vessels were cannulated and maintained at constant distending pressure and 37 °C under a two photon laser scanning microscope. They were then subsequently exposed to first 100 nM linear ET-1 (ETB-agonist) tagged with Oregon Green 488 (OG488) and then to 16 nM intact ET-1 (ETA/ETB-agonist) tagged with the rhodamine dye TAMRA. After incubation with the labeled ligands, the arterial smooth muscle cells in the tunica media were efficiently stained and became visible under the two photon microscope. Wrinkling of the autofluorescent internal and external elastic laminae accompanied agonist-induced constriction. TAMRA-ET-1 bound to all smooth muscle cells with a homogeneous cytoplasmic distribution whereas similar staining was observed for labeled linear ET-1 but only on some group of cells. Fluorescence lifetime measurements were employed to probe the interaction of the two receptor subtypes. Fluorescence lifetime of OG488, which acted as a donor, was reduced in the presence of TAMRA, from 2.8 ps to 2.3 ps, which indicates a fluorescence resonant energy transfer (FRET), a phenomenon which can take place only if the receptors are in close proximity (< 10 nm). The methodology that is introduced by these preliminary observations may be useful to asses ET-receptor heterodimerization in biopsies from relevant experimental animal models and human patients.

doi:10.1016/j.lfs.2013.12.190

Sympathetic endothelin A receptors contribute to the development of heart failure

Johannes P. Backsa f, Lorenz L. Lehmanna, Julia Rostoskya, Sebastian J. Bussa, Walter Mierb, Michael D. Schneiderc, Rosanna Parlatod, Hermann-Josef Groenee, Masashi Yanagisawaf, Uwe Haberkornb, Hugo A. Katusa

aCardiology, Heidelberg University, Heidelberg, Germany

bDepartment of Nuclear Medicine, University Hospital, Heidelberg, Germany

cBritish Heart Foundation Centre of Research Excellence,

Imperial College London, United Kingdom

dInstitute of Applied Physiology, University ofUlm, Ulm, Germany

eDepartment of Molecular Pathology, German Cancer Research Center (DKFZ),

Heidelberg, Germany

fHHMI and Dept. of Molecular Genetics, UTSW Medical Center at Dallas, Dallas, USA

E-mail address: johannes.backs@med.uni-heidelberg.de (J.P. Backs)

In preclinical heart failure (HF) models, endothelin receptor A (ETA) antagonists (ETAi) attenuated the disease progression. However, clinical HF trials failed to demonstrate beneficial effects on cardiac function and prognosis. We hypothesized that established HF drugs such as adrenergic receptor blockers interfere with the mechanism of action of ETAi. Here we report, that mice lacking ETA selectively in sympathetic neurons (SN-KO) showed less adverse structural remodeling and cardiac dysfunction in response to pathological pressure overload induced by transverse aortic constriction (TAC). In contrast, mice lacking ETA selectively in cardiomyocytes (CM-KO) were not protected against HF. TAC led to a disturbed sympathetic nerve function as measured by cardiac norepinephrine (NE) tissue levels and [1241]-M1BG PET, which was prevented in SN-KO. In co-cultures of cardiomyocytes (CMs) and sympathetic neurons (SNs), endothelin-1 (ET1) led to a massive NE release and exaggerated CM hypertrophy as compared to CM monocultures. ETA-deficient CMs gained a hypertrophic response through wild type SNs but ETA-deficient SNs failed to mediate exaggerated CM

Abstracts

hypertrophy. Furthermore, ET1 mediated its effects indirectly via NE in CM-SN co-cultures through adrenergic receptors and histone deacetylases, resulting in activation of the pro-hypertrophic transcription factor MEF2. In conclusion, sympathetic ETA amplifies ET1 effects on CMs through adrenergic neurotransmission. In accordance to our initial hypothesis, anti-adrenergic therapies may blunt potential beneficial effects of ETAi. These findings call for a personalized strategy to identify patients that could benefit from ETAi.

doi:10.1016/j.lfs.2013.12.191

Mouse Mast Cell Protease-4-dependent production of ET-1 (1-31) and of plaque progression in an Apolipoprotein E knock-out mouse model of spontaneous atherosclerosis

Martin Houdea, Walid Semaana, Louisane Desbiensa, Zhipeng Youb, Adel G. Schwertanib, Gunnar Pejlerc, Shinji Takaid, Pedro D'Orléans-Justea

aDepartment of Pharmacology, Universite de Sherbrooke, Sherbrooke, QC, Canada

bDepartment of Medicine, McGill University, Montreal, QC, Canada cDepartment of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden dDepartment of Pharmacology, University of Osaka, Osaka, Japan E-mail address: martin.houde@usherbrooke.ca (M. Houde)

The murine homologue to human chymase, the mouse Mast Cell Protease-4 (mMCP-4), activates the pro-forms of angiotensin-II and endothelin-1 (ET-1) in vivo; both peptides being well-established in cardiovascular diseases. In the present study we postulated that mMCP-4-dependent synthesis of ET-1 plays an important role in the development of atherosclerosis in the Apolipoprotein E knock out mouse model (ApoE KO). Peritoneal mast cells were collected from C56BL/6J wild-type (WT), mMCP-4 KO and ApoE KO mice and their granular contents were assayed for the enzymatic processing of the fluorogenic substrate Suc-Val-Val-Pro-Phe-amidomethylcoumarin. WT and ApoE KO derived samples produced a TY-51469 (specific chymase inhibitor) sensitive fluorescence, but not in mMCP-4 KO samples. Via HPLC detection, a TY-51469-sensitive conversion of big ET-1 to ET-1 (1-31) was monitored in mast cell homogenates. Homogenate samples from ApoE KO mice showed significant increases in ET-1 (1-31) production when compared to extracts from WT mice (milliAU x time (s), WT: 763 ± 124; ApoE KO: 1756 ± 339, n = 7; P = 0.018). Finally, Sudan IV staining of aortas from 27 to 30 week old male mice on chow diet showed that the repression of mMCP-4 in APOE KO mice (APOE/ mMCP-4 dKO) reduced by 65% the atherosclerotic lesion area found in ApoE KO mice (ApoE KO: 7.45 ± 1.31%; ApoE/mMCP-4 dKO: 2.67 ± 0.64%, n = 9-10, P = 0.004). These results suggest an increased contribution role of mMCP-4 in the synthesis of ET-1 in mast cells derived from ApoE KO mice and the pivotal role of that chymase isoform in the development of atherosclerosis. (Funded by CIHR).

doi:10.1016/j.lfs.2013.12.192