Protein kinase A mediated stimulation of activating transcription factor 3 by hypertrophic stimuli in cardiomyocytes

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1 Protein kinase A mediated stimulation of activating transcription factor 3 by hypertrophic stimuli in cardiomyocytes Elina Koivisto, MD, PhD Institute of Biomedicine, Department of Pharmacology and Toxicology University of Oulu, Finland

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Normal heart Hypertrophic response Remodeling

3 Modified from: Heineke & Molkentin. Nat Rev Mol Cell Biol 2006; 7: Cardiac hypertrophy and development of heart failure Cardiac pumping capacity (%) Normal heart Hypertrophic response Remodeling Left ventricular hypertrophy Heart failure 0 Hemodynamic load

4 Alterations in cardiomyocyte gene expression in cardiac hypertrophy and heart failure Modified from: Hoshijima & Chien. Clin Invest 2002; 109:

5 Alterations in cardiomyocyte gene expression in cardiac hypertrophy and heart failure Modified from: Hoshijima & Chien. Clin Invest 2002; 109:

6 ATF3 is a stress-activated immediate early gene Member of ATF/CREB family ATF3 in the heart: Activated by ischemia, ischemia/reperfusion, oxidative stress (Chen et al. Mol Cell Biol 1996; 16: ; Yin et al. J Biol Chem 1997; 272: ; Clerk et al. Physiol Genomics 2007; 29: ) Activated by hypertrophic agonists Endothelin-1 (Clerk et al. Adv Enzyme Regul 2009; 49: 30-42) Phenylephrine (Hasin et al. Basic Res Cardiol 2010; 106 :175-87) Isoprenaline (Hasin et al. Basic Res Cardiol 2010; 106 :175-87) Angiotensin II (Kehat et al. Cardiovasc Res 2006; 70: ) ATF3 reduced cardiac contractility and cardiac function (Okamoto et al. Am J Pathol 2001; 159: ) ATF3 decreased apoptosis (Nobori et al. J Mol Cell Cardiol 2002; 34: ) ATF3 decreased IL-6 expression (Clerk et al. Adv Enzyme Regul 2009; 49: 30-42)

7 Purpose of the study Signaling pathways mediating the activation of ATF3 by mechanical stretch and endothelin-1? Cardiac gene regulation by ATF3 overexpression in vitro and in vivo?

8 Cyclic mechanical stretching of neonatal rat cardiomyocyte cell cultures

9 Cyclic mechanical stretching of neonatal rat cardiomyocyte cell cultures p38 inhibitor SB ERK inhibitor PD98059 PKA inhibitor H-89

10 Mechanical stretch and ET-1 (100 nm) induce ATF3 and BNP gene expression

11 Mechanical stretch and ET-1 (100 nm) induce ATF3 and BNP gene expression

12 Stretch and ET-1 (100 nm) -induced ATF3 mrna and protein expression is partly mediated through PKA and ERK

13 Stretch and ET-1 (100 nm) -induced ATF3 mrna and protein expression is partly mediated through PKA and ERK

14 Stretch and ET-1 (100 nm) -induced ATF3 mrna and protein expression is partly mediated through PKA and ERK

15 Isoprenaline (100 nm) -induced ATF3 protein expression is mediated through PKA

16 p38a-isoform regulates ATF3 activity

17 p38a-isoform regulates ATF3 activity

18 p38a-isoform regulates ATF3 activity

19 p38a-isoform regulates ATF3 activity

20 ATF3 overexpression induces NF-KB and Nkx-2.5 binding activity and inhibits IL-6 and PAI-1 mrna transcription

21 ATF3 overexpression induces NF-KB and Nkx-2.5 binding activity and inhibits IL-6 and PAI-1 mrna transcription

22 ATF3 overexpression induces NF-KB and Nkx-2.5 binding activity and inhibits IL-6 and PAI-1 mrna transcription

23 ATF3 overexpression induces NF-KB and Nkx-2.5 binding activity and inhibits IL-6 and PAI-1 mrna transcription

24 Conclusions ATF3 activation by mechanical stretch and ET-1 is partly mediated through PKA as well as ERK by posttranscriptional mechanisms

25 Conclusions ATF3 activation by mechanical stretch and ET-1 is partly mediated through PKA as well as ERK by posttranscriptional mechanisms p38a isoform regulates ATF3 activity

26 Conclusions ATF3 activation by mechanical stretch and ET-1 is partly mediated through PKA as well as ERK by posttranscriptional mechanisms p38a isoform regulates ATF3 activity ATF3 overexpression Induces NF-KB and Nkx-2.5 binding activity Inhibits PAI-1 mrna transcription in vitro and in vivo Inhibits IL-6 mrna transcription in vitro

27 Conclusions ATF3 activation by mechanical stretch and ET-1 is partly mediated through PKA as well as ERK by posttranscriptional mechanisms p38a isoform regulates ATF3 activity ATF3 overexpression Induces NF-KB and Nkx-2.5 binding activity Inhibits PAI-1 mrna transcription in vitro and in vivo Inhibits IL-6 mrna transcription in vitro Cardioprotective role for ATF3?

28 Acknowledgements Anne-Mari Moilanen Jaana Rysä Heikki Tokola Jani Aro Harri Pennanen Hanna Säkkinen Leena Kaikkonen Alicia Jurado Marja Arbelius Sirpa Rutanen Kirsi Salo Professor Heikki Ruskoaho

Characterization of the Regulatory Mechanisms of Activating Transcription Factor 3 by Hypertrophic Stimuli in Rat Cardiomyocytes

https://helda.helsinki.fi Characterization of the Regulatory Mechanisms of Activating Transcription Factor 3 by Hypertrophic Stimuli in Rat Cardiomyocytes Koivisto, Elina 2014-08-19 Koivisto, E, Acosta,