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Acta Physiologica 2013; Volume 207, Supplement 694
92nd Annual Meeting of the German Physiological Society
3/2/2013-3/5/2013
Heidelberg, Germany
PROLYL-4-HYDROXYLASE DOMAIN (PHD) PROTEINS AND THE CARDIAC SYSTEM: NEW ASPECTS OF CARDIAC CYTOPROTECTION
Abstract number: S24
Hesse
1
A., Hölscher
1
M., Silter
1
M., Katschinski
1
D.M.,
Zieseniss
1
*A.
1
Department of Cardiovascular Physiology, University Medical Center Goettingen, Georg-August University Goettingen, Germany
Cardiac ischemia is a major leading cause of cardiomyopathy and of high relevance for mortality in Western countries. New therapeutic strategies targeting the affected cardiomyocytes are highly wanted to purposefully control cytoprotective pathways in the heart. Ischemic diseases represent a quite obvious disease entity to be addressed by modulating the PHD (prolyl-4-hydroxylase domain)/ HIF (hypoxia inducible factor) signaling pathway which is known to regulate a plethora of genes that affect cell survival and metabolism in adverse conditions. To analyze the importance of HIF-1? stabilization and the PHD isoforms for cardiac physiology and the response of the myocardium towards hypoxia, we have knocked out PHD2 in cardiomyocytes (
cPhd2-/-)
which resulted in HIF-1? stabilization and activation of HIF target genes in the heart. Interestingly, we observed a significantly increased cardiac capillary area and a shift in cardiac metabolism toward glycolysis in
cPhd2-/-
mice. Similar changes were seen in our cardiac-specific HIF-1? transgenic mouse model (
Hif-1?tg
). Excitingly, these alterations mediated a beneficial, cell protective effect after acute myocardial infarction in
cPhd2-/-
and
Hif-1?tg
mice. However, with ageing HIF-1? stabilization becomes detrimental for cardiac function. Therefore, our results indicate that short-term activation of HIF-1 is beneficial and may be used in therapeutic strategies, prolonged activation of HIF-1 over time drives the development of cardiomyopathy.
Besides being the major regulators of HIF activity, there is also increasing evidence of roles for individual PHDs in regulating cellular processes independently of HIF-1 interactions. So far three PHD (PHD1-3) isoforms are known of which PHD3 is upregulated in response to hypoxia e.g. after myocardial infarction. To further understand the molecular role of PHD3 in the heart we have generated cardiomyocyte-specific PHD3 knock out (
cPhd3-/-
) and PHD3 transgenic (
PHD3tg
) mice. Unlike the
cPhd2-/-
mice the
cPhd3-/-
mice do not show a strong HIF-1? protein stabilization. However ATF-4 (activating transcription factor-4) is stabilized in the hearts of
cPhd3-/-
mice and ATF-4 specific target genes are induced. These data offer the intriguing hypothesis that inhibition of PHD2 versus PHD3 affects different signal transduction pathways and therefore might be used for therapeutic purposes differentially.
To cite this abstract, please use the following information:
Acta Physiologica 2013; Volume 207, Supplement 694 :S24