Changes induced with transgenic cardiac HIF-1α possibly mediate beneficial effects in the short term; however, with increased mechanical load and ageing they become detrimental for cardiac function. Together with the finding of increased HIF-1α protein levels in samples from human patients with cardiomyopathy, these data indicate that chronic HIF-1α stabilization drives autonomous pathways that add to disease progression.

Prolylhydroxylase domain proteins (PHD) are cellular oxygen-sensing molecules that regulate the stability of the ␣-subunit of the transcription factor hypoxia inducible factor (HIF)-1. HIF-1 affects cardiac development as well as adaptation of the heart toward increased pressure overload or myocardial infarction. We have disrupted PHD2 in cardiomyocytes (cPhd ؊/؊ ) When oxygen availability is impaired, the resulting hypoxia activates homeostatic mechanisms at the systemic and cellular level (1). Hypoxia-inducible factors (HIFs) 2 are essential players in these responses because they regulate the transcription of a large number of genes that affect a myriad of cellular processes, including angiogenesis, metabolism, cell survival, and oxygen delivery (2). HIF is a heterodimeric protein comprising the oxygen-sensitive ␣-subunit HIF-1␣ or the more cell type-specifically expressed HIF-2␣ or HIF-3␣ and the oxygen-insensitive ␤-subunit (3). In the presence of oxygen, HIF␣ becomes hydroxylated at two critical proline residues by prolylhydroxylase domain (PHD) enzymes (4, 5). The PHD protein family responsible for HIF␣ regulation consists of three members called prolylhydroxylase domain (PHD)1, PHD2, and PHD3 (6, 7). Following prolyl-4-hydroxylation of the critical prolyl residues under normoxic conditions, the ubiquitin ligase von Hippel-Lindau tumor suppressor protein recognizes ⌯⌱F-1␣ subunits and targets them for rapid ubiquitination and proteasomal degradation (8 -10).Based on the ubiquitous expression pattern and its dominant effect in normoxia, it had to be assumed that PHD2 is the most critical HIF-1␣-regulating PHD isoform in most tissues (11)(12)(13). This notion, learned from in vitro studies, was confirmed by the up to now available genetically modified Phd2 mouse models (14). Phd2 knock-out embryos die between embryonic day (E) 12.5 and E14.5 (15). This time point coincides with the increased levels of PHD2 in wild-type (wt) mice starting from E9.0. A major role of PHD2 in regulating the HIF system is further underscored by mouse models with a somatic Phd2 Ϫ/Ϫ knock out, which enable to analyze the in vivo function of PHD2 in the adult mice. Two independent inducible Phd2 Ϫ/Ϫ mouse models were developed by Takeda et al. (16) and Minamishima et al. (17). The phenotype of these mice most obviously resembles the consequences of HIF␣ overexpression with increased angiogenesis, erythropoiesis, and extramedullar hematopoiesis (17,18). Most interestingly, these mice also develop a cardiac phenotype with symptoms of dilated cardiomyopathy. In the heart, HIF-1␣ and thereby also the PHDs are known to influence key components of heart development, morphogenesis, and function (19,20). Long term activation of HIF-1␣ in the heart seems to activate detrimental pathways resulting in the development of heart failure (21). Thus, it is tempting to speculate that loss of PHD2 in the heart is responsible for the dilated cardiomyopathy as observed in the inducible Phd2 Ϫ/Ϫ mice. However, because these mice also develop an inc...

The hypoxia-inducible factor (HIF)-1 is critically involved in the cellular adaptation to a decrease in oxygen availability. The influence of HIF-1α for the development of cardiac hypertrophy and cardiac function that occurs in response to sustained pressure overload has been mainly attributed to a challenged cardiac angiogenesis and cardiac hypertrophy up to now. Hif-1α+/+ and Hif-1α+/− mice were studied regarding left ventricular hypertrophy and cardiac function after being subjected to transverse aortic constriction (TAC). After TAC, both Hif-1α+/+ and Hif-1α+/− mice developed left ventricular hypertrophy with increased posterior wall thickness, septum thickness and increased left ventricular weight to a similar extent. No significant difference in cardiac vessel density was observed between Hif-1α+/+ and Hif-1α+/− mice. However, only the Hif-1α+/− mice developed severe heart failure as revealed by a significantly reduced fractional shortening mostly due to increased end-systolic left ventricular diameter. On the single cell level this correlated with reduced myocyte shortenings, decreased intracellular Ca2+-transients and SR-Ca2+ content in myocytes of Hif-1a+/− mice. Thus, HIF-1α can be critically involved in the preservation of cardiac function after chronic pressure overload without affecting cardiac hypertrophy. This effect is mediated via HIF-dependent modulation of cardiac calcium handling and contractility.Electronic supplementary materialThe online version of this article (doi:10.1007/s00424-009-0748-x) contains supplementary material, which is available to authorized users.