Prolyl-hydroxylase domain (PHD) proteins are cellular oxygen sensing molecules, which regulate the stability of the a-subunit of the transcription factor Hypoxia inducible factor (HIF)-1. HIF-1 affects cardiac development as well as adaptation of the heart towards increased pressure overload or myocardial infarction. While PHD enzymes are 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. We have shown before that cardiomyocyte-specific PHD2 knock out mice ( cPhd2^-/- ) are protected against acute ischemia [1] but develop heart failure with aging. 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 (tgPHD3) mice. Under resting conditions the mice show no gross abnormalities in heart structure and function. Unlike the cPhd2^-/- mice the cPhd3^-/- mice do not show a strong HIF-1a 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. After ligation of the left anterior descending artery, the cPhd3^-/- mice showed no differences compared to wt littermates. Interestingly, in tgPHD3 mice after acute ischemia the total infarct size was significantly larger than in wt control mice.

In the future we will further analyse the cardioprotective potential of the HIF-1a and ATF-4 protein stabilization in cPhd2^-/- and cPhd3^-/- mice by conducting ischemia reperfusion experiments.

[1] Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury. Hölscher M, Silter M, Krull S, von Ahlen M, Hesse A, Schwartz P, Wielockx B, Breier G, Katschinski DM, Zieseniss A. J Biol Chem. 2011 Apr 1;286(13): 11185-94.

* These authors contributed equally to this work.