Androgens in cardiac hypertrophy
Final Report Abstract
In this project we generated novel rodent models to characterize the functions of androgens in cardiovascular diseases. Mice which lack the androgen receptor (AR) specifically in all cardi- omyocytes could not be established because the two Cre-recombinase expressing mouse strains we employed for this purpose either did not express in all cardiomyocytes or expressed in too many other cell types. However, we could establish mice lacking AR in macrophages and are analyzing these animals for cardiovascular phenotypes. Moreover, transgenic rats overexpressing AR specifically in cardiomyocytes, TGR(MLC2AR) could be generated. These animals developed sex-specific alterations in cardiac rhythm. Telemetric electrocardi- ography (ECG) revealed a shortened QTc interval in female transgenic rats and a prolonged one in males compared to control animals. Transcriptome analysis of hearts from male and female TGR(MLC2AR) rats by next generation sequencing detected the inward rectifying potassium channel, KCNK1, as being over expressed only in male transgenic rats but not in females rendering it a good candidate responsible for the observed alterations in theECG. In parallel, a technology was established to assess rapid non-genomic signaling of androgens in cardiomyocyte like cells. ERK1/2 phosphorylation was time- and dose-dependently in- creased in AC16 cells by treatment with the androgen dihydrotestosterone. This method needs to be further optimized to be used in a high-throughput assay for the discovery of proteins involved in rapid androgen signaling incardiomyocytes.
Publications
- Controlling cardiomyocyte length: The role of renin and PPAR-γ. Cardiovasc Res. 2011; 89:344-352
Hinrichs S, Heger J, Schreckenberg R, Wenzel S, Euler G, Arens C, Bader M, Rosenkranz S, Caglayan E, Schluter KD
(See online at https://doi.org/10.1093/cvr/cvq313) - SDF-1alpha as a therapeutic stem cell homing factor in myocardial infarction. Pharmacol Ther. 2011, 129:97-108
Ghadge S, Mühlstedt S, Özcelik C, Bader M
(See online at https://doi.org/10.1016/j.pharmthera.2010.09.011) - Angiotensin-(1-7) receptor Mas is an essential modulator of extracellular matrix protein expression in the heart. Regul Pept. 2012, 175:30-42
Gava E, de Castro CH, Ferreira AJ, Colleta H, Melo MB, Alenina N, Bader M, Oliveira LA, Kitten GT, Santos RA
(See online at https://doi.org/10.1016/j.regpep.2012.01.001) - Exercise induces renin-angiotensin system unbalance and high collagen expression in the heart of Mas-deficient mice. Peptides. 2012, 38:54-61
Guimaraes GG, Santos SH, Pimenta-Veloso EP, Oliveira ML, Motta DF, Martins AS, Bader M, Santos RA, Campagnole-Santos MJ
(See online at https://doi.org/10.1016/j.peptides.2012.05.024) - Functional cross-talk between aldosterone and angiotensin-(1-7) in ventricular myocytes. Hypertension 2013;61:425-430
de Almeida PW, de Freitas LR, de Morais Gomes ER, Rocha-Resende C, Roman-Campos D, Gondim AN, Gavioli M, Lara A, Parreira A, de Azevedo Nunes SL, Alves MN, Santos SL, Alenina N, Bader M, Resende RR, Dos Santos CJ, Dos Santos RA, Guatimosim S
(See online at https://doi.org/10.1161/HYPERTENSIONAHA.111.199539) - Effect of Angiotensin(1-7) on Heart Function in an Experimental Rat Model of Obesity. Front Physiol. 2015 Dec 21;6:392
Blanke K, Schlegel F, Raasch W, Bader M, Dähnert I, Dhein S, Salameh A
(See online at https://doi.org/10.3389/fphys.2015.00392) - Cardiac angiotensin-(1-12) expression and systemic hypertension in rats expressing the human angiotensinogen gene. Am J Physiol Heart Circ Physiol. 2016 Apr 15;310(8):H995-H1002
Ferrario CM, VonCannon J, Jiao Y, Ahmad S, Bader M, Dell'Italia LJ, Groban L, Varagic J
(See online at https://doi.org/10.1152/ajpheart.00833.2015) - Cardiomyocyte-derived CXCL12 is not involved in cardiogenesis but plays a crucial role in myocardial infarction. J Mol Med (Berl). 2016 Jun 1
Mühlstedt S, Ghadge SK, Duchene J, Qadri F, Järve A, Vilianovich L, Popova E, Pohlmann A, Niendorf T, Boyé P, Özcelik C, Bader M
(See online at https://doi.org/10.1007/s00109-016-1432-1) - Effects of ACE2 deficiency on physical performance and physiological adaptations of cardiac and skeletal muscle to exercise. Hypertens Res. 2016 Apr 7
Motta-Santos D, Dos Santos RA, Oliveira M, Qadri F, Poglitsch M, Mosienko V, Kappes Becker L, Campagnole-Santos MJ, M Penninger J, Alenina N, Bader M
(See online at https://doi.org/10.1038/hr.2016.28)
