TY - JOUR
T1 - Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling
AU - Lehmann, Lorenz H.
AU - Rostosky, Julia S.
AU - Buss, Sebastian J.
AU - Kreusser, Michael M.
AU - Krebs, Jutta
AU - Mier, Walter
AU - Enseleit, Frank
AU - Spiger, Katharina
AU - Hardt, Stefan E.
AU - Wieland, Thomas
AU - Haass, Markus
AU - Lüscher, Thomas F.
AU - Schneider, Michael D.
AU - Parlato, Rosanna
AU - Gröne, Hermann Josef
AU - Haberkorn, Uwe
AU - Yanagisawa, Masashi
AU - Katus, Hugo A.
AU - Backs, Johannes
PY - 2014/9/16
Y1 - 2014/9/16
N2 - In preclinical studies, endothelin receptor A (ETA) antagonists (ETAi) attenuated the progression of heart failure (HF). However, clinical HF trials failed to demonstrate beneficial effects of ETAi. These conflicting data may be explained by the possibility that established HF drugs such as adrenergic receptor blockers interfered with the mechanism of ETAi action in clinical trials. Here we report that mice lacking ETAonly 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 ETAonly in cardiomyocytes (CM-KO) were not protected. TAC led to a disturbed sympathetic nerve function as measured by cardiac norepinephrine (NE) tissue levels and [124I]-metaiodobenzylguanidine-PET, which was prevented in SN-KO. In a rat model of HF, ETAi improved cardiac and sympathetic nerve function. In cocultures of cardiomyocytes (CMs) and sympathetic neurons (SNs), endothelin-1 (ET1) led to a massive NE release and exaggerated CM hypertrophy compared with CM monocultures. ETA-deficient CMs gained a hypertrophic response through wild-type SNs, but ETA-deficient SNs failed to mediate exaggerated CM hypertrophy. Furthermore, ET1 mediated its effects indirectly via NE in CM-SN cocultures through adrenergic receptors and histone deacetylases, resulting in activation of the prohypertrophic transcription factor myocyte enhancer factor 2. In conclusion, sympathetic ETAamplifies ET1 effects on CMs through adrenergic signaling pathways. Thus, anti-adrenergic therapies may blunt potentially beneficial effects of ETAi. Taken together, this may indicate that patients with β blocker intolerance or disturbed sympathetic nerve function could be evaluated for a potential benefit from ETAi.
AB - In preclinical studies, endothelin receptor A (ETA) antagonists (ETAi) attenuated the progression of heart failure (HF). However, clinical HF trials failed to demonstrate beneficial effects of ETAi. These conflicting data may be explained by the possibility that established HF drugs such as adrenergic receptor blockers interfered with the mechanism of ETAi action in clinical trials. Here we report that mice lacking ETAonly 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 ETAonly in cardiomyocytes (CM-KO) were not protected. TAC led to a disturbed sympathetic nerve function as measured by cardiac norepinephrine (NE) tissue levels and [124I]-metaiodobenzylguanidine-PET, which was prevented in SN-KO. In a rat model of HF, ETAi improved cardiac and sympathetic nerve function. In cocultures of cardiomyocytes (CMs) and sympathetic neurons (SNs), endothelin-1 (ET1) led to a massive NE release and exaggerated CM hypertrophy compared with CM monocultures. ETA-deficient CMs gained a hypertrophic response through wild-type SNs, but ETA-deficient SNs failed to mediate exaggerated CM hypertrophy. Furthermore, ET1 mediated its effects indirectly via NE in CM-SN cocultures through adrenergic receptors and histone deacetylases, resulting in activation of the prohypertrophic transcription factor myocyte enhancer factor 2. In conclusion, sympathetic ETAamplifies ET1 effects on CMs through adrenergic signaling pathways. Thus, anti-adrenergic therapies may blunt potentially beneficial effects of ETAi. Taken together, this may indicate that patients with β blocker intolerance or disturbed sympathetic nerve function could be evaluated for a potential benefit from ETAi.
KW - Epigenetic regulation
KW - HDACs
KW - Norepinephrine reuptake
KW - Sympathetic nervous system
KW - β adrenergic signaling
UR - http://www.scopus.com/inward/record.url?scp=84907192439&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907192439&partnerID=8YFLogxK
U2 - 10.1073/pnas.1409026111
DO - 10.1073/pnas.1409026111
M3 - Article
C2 - 25197047
AN - SCOPUS:84907192439
SN - 0027-8424
VL - 111
SP - 13499
EP - 13504
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 37
ER -