Essential role of sympathetic endothelin A receptors for adverse cardiac remodeling

Lorenz H. Lehmann, Julia S. Rostosky, Sebastian J. Buss, Michael M. Kreusser, Jutta Krebs, Walter Mier, Frank Enseleit, Katharina Spiger, Stefan E. Hardt, Thomas Wieland, Markus Haass, Thomas F. Lüscher, Michael D. Schneider, Rosanna Parlato, Hermann Josef Gröne, Uwe Haberkorn, Masashi Yanagisawa, Hugo A. Katus, Johannes Backs

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)13499-13504
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number37
StatePublished - Sep 16 2014


  • Epigenetic regulation
  • HDACs
  • Norepinephrine reuptake
  • Sympathetic nervous system
  • β adrenergic signaling

ASJC Scopus subject areas

  • General


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