Author + information
- Received June 29, 2011
- Revision received August 17, 2011
- Accepted September 13, 2011
- Published online January 24, 2012.
- Georgios Kararigas, PhD⁎,⁎ (, )
- Virginie Bito, PhD§,
- Hanna Tinel, PhD‡,
- Eva Becher, PhD⁎,
- Istvan Baczko, MD, PhD∥,
- Christoph Knosalla, MD†,
- Barbara Albrecht-Küpper, PhD‡,
- Karin R. Sipido, MD, PhD§ and
- Vera Regitz-Zagrosek, MD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Georgios Kararigas or Dr. Vera Regitz-Zagrosek, Institute of Gender in Medicine and Center for Cardiovascular Research, Charite University Hospital, Hessische Strasse 3-4, 10115 Berlin, Germany
Objectives This study investigated the effects of 17β-estradiol (E2) on gene regulation in human cardiac tissues. We hypothesized that a candidate E2 effect is cardiomyocyte (CM)- and sex-specific, conserved between humans and mice, and that E2 impairs contractile function in male CMs only.
Background Both men and women produce E2 locally from androgenic precursors. E2 regulates cardiovascular function, but specific mechanisms, protective or harmful, are not fully understood.
Methods We performed genome-wide expression profiling of E2-treated cardiac tissues from men and women, and studied gene expression and function in CMs from hearts of male and female E2-treated mice.
Results We found 36 E2-dependent genes regulated in a sex-specific manner. Of these, after E2 exposure, the myosin regulatory light chain interacting protein (MYLIP) gene was induced in tissues of men only. Focusing on Mylip and employing isolated mouse CMs, we confirmed our hypotheses that the E2 effect is CM- and sex-specific and conserved between humans and mice. The E2-treatment led to impaired contractile function in male CMs only, which was characterized by increased Mylip mRNA and protein levels, and decreased myosin regulatory light chain (Mrlc) protein. Our report is the first to our knowledge to show that cardiac Mrlc is an in vivo substrate for Mylip, leading to augmented Mrlc ubiquitination. Of relevance, we found that MYLIP expression levels rise with increasing age in hearts of men.
Conclusions E2 directly influences cardiac gene regulation, and E2 actions may be different between the sexes. Since E2 levels rise in older and/or obese men, pharmacological targeting of MYLIP in men with elevated E2 levels could possibly decrease their risk for the development or progression of cardiovascular disease.
This work was supported by a Marie Curie Fellowship (to Dr. Kararigas) from the European Union (EU) through the program CARDIOVASC grant No. MEST-CT-2005-020268, the EU-funded EUGeneHeart research project grant No. LSHM-CT-2005-018833 (to Drs. Sipido and Regitz-Zagrosek), a grant from the German Research Foundation (DFG) (FG1054/1 to Dr. Regitz-Zagrosek), and a Travel Fellowship from the Boehringer Ingelheim Fonds (to Dr. Kararigas). Drs. Tinel and Albrecht-Küpper are employees of Bayer HealthCare. Dr. Regitz-Zagrosek has a research agreement with Bayer HealthCare; and has received speaker honorarium from Bayer HealthCare, Berlin Chemie AG, and Dr. Willmar Schwabe GmbH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Becher's current address is the German Aerospace Center, Bonn, Germany.
- Received June 29, 2011.
- Revision received August 17, 2011.
- Accepted September 13, 2011.
- American College of Cardiology Foundation