Obesity is a major public health problem, predisposing subjects to metabolic syndrome, type 2 diabetes, and cardiovascular diseases. Specific prolyl 4-hydroxylases (P4Hs) regulate the stability of the hypoxia-inducible factor (HIF), a potent governor of metabolism, with isoenzyme 2 being the main regulator. We investigated whether HIF-P4H-2 inhibition could be used to treat obesity and its consequences. Hif-p4h-2–deficient mice, whether fed normal chow or a high-fat diet, had less adipose tissue, smaller adipocytes, and less adipose tissue inflammation than their littermates. They also had improved glucose tolerance and insulin sensitivity. Furthermore, the mRNA levels of the HIF-1 targets glucose transporters, glycolytic enzymes, and pyruvate dehydrogenase kinase-1 were increased in their tissues, whereas acetyl-CoA concentration was decreased. The hepatic mRNA level of the HIF-2 target insulin receptor substrate-2 was higher, whereas that of two key enzymes of fatty acid synthesis was lower. Serum cholesterol levels and de novo lipid synthesis were decreased, and the mice were protected against hepatic steatosis. Oral administration of an HIF-P4H inhibitor, FG-4497, to wild-type mice with metabolic dysfunction phenocopied these beneficial effects. HIF-P4H-2 inhibition may be a novel therapy that not only protects against the development of obesity and its consequences but also reverses these conditions.

Ischemic heart disease (IHD) is the leading cause of death worldwide. Novel cardioprotective strategies are therefore required to improve clinical outcomes in patients with IHD. Although a large number of novel cardioprotective strategies have been discovered in the research laboratory, their translation to the clinical setting has been largely disappointing. The reason for this failure can be attributed to a number of factors including the inadequacy of the animal ischemia–reperfusion injury models used in the preclinical cardioprotection studies and the inappropriate design and execution of the clinical cardioprotection studies. This important issue was the main topic of discussion of the UCL-Hatter Cardiovascular Institute 6th International Cardioprotection Workshop, the outcome of which has been published in this article as the “Hatter Workshop Recommendations”. These have been proposed to provide guidance on the design and execution of both preclinical and clinical cardioprotection studies in order to facilitate the translation of future novel cardioprotective strategies for patient benefit.

The hypothesis that L-DOPA therapy in Parkinson's disease may augment neuronal damage and thus accelerate the progression of the disease remains controversial. In this study, we demonstrate that L-DOPA induces death of catecholaminergic cells in vitro via an active program of apoptosis. Treatment of PC12 cells with clinically applicable concentrations of L-DOPA (25-100 ,uM) induced cell death via a mechanism which exhibited morphological and biochemical characteristics of apoptosis, including chromatin condensation, membrane blebbing, and internucleosomal DNA fragmentation. L-DOPA-induced apoptosis was cell and drugtype specific. Toxicity is an intrinsic property of the drug molecule since it was not suppressed by inhibiting conversion of L-DOPA to dopamine. However, L-DOPA toxicity was inhibited by antioxidants, suggesting that activation of apoptosis is mediated by oxygen radicals. Our finding that L-DOPA-induced cell death in vitro occurs via apoptosis explains the lack of evidence supporting its toxicity in vivo, since apoptotic neurons are rapidly phagocytosed in vivo without causing damage to surrounding tissue. Furthermore, since apoptosis is an active cellular program which can be modulated, we suggest clinical approaches for decreasing L-DOPA toxicity, thus preventing acceleration of neuronal damage in Parkinson's disease. (J. Clin. Invest. 1995Invest. . 95:2458Invest. -2464

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Key Points• HIF-1␣ protein stabilization increases HSC quiescence in vivo.• HIF-1␣ protein stabilization increases HSC resistance to irradiation and accelerates recovery. IntroductionTo remain in an undifferentiated state, hematopoietic stem cells (HSCs) need be lodged in specific niches of the BM where they can preserve their essential capacity to self-renew and reconstitute the whole hematopoietic and immune systems on transplantation. 1-2 In mice 3 and humans, 4 the BM contains 2 pools of HSCs: (1) a quiescent pool that divides very infrequently approximately every 145 days to self-renew and maintain a genetic reserve and (2) an activated pool that divides more frequently for the daily replacement of hematopoietic progenitor cells (HPCs), blood leukocytes, erythrocytes, and platelets. Molecular components of HSC niches are critical to maintaining the correct balance among quiescence, self-renewing proliferation, and differentiation of HSCs. It has been found recently that, in addition to the stromal cells forming niches and the arrays of essential mediators they secrete, the physicochemical conditions within niches are critical to maintaining HSC quiescence and self-renewal. 5 For example, the most quiescent HSCs capable of serial reconstitution in serial transplantations reside in niches very poorly perfused by the circulating blood, whereas more active and proliferative HSCs capable of only a single round of transplantation or reconstitution reside in more perfused niches. 6 A direct consequence of low perfusion could be increased local hypoxia. Indeed, the oxygenation rate of a tissue is dependent on how rapidly oxygen solubilized in the circulating blood perfuses into the tissue and how rapidly this oxygen is consumed by cells in an active metabolic state. [7][8] Similar to the BM, solid tumors are sites of rapid regeneration and cell division. Analyses of blood perfusion and hypoxia in solid tumors have shown that areas that are poorly perfused are stained by the hypoxia sensitive marker pimonidazole, suggesting a hypoxic state, 9 and contain tumor stem cells. [10][11] Similarly, the endosteal region of the mouse BM, which is known to harbor niches containing quiescent HSCs,3,[12][13][14][15] is also stained by pimonidazole in steady-state conditions, also suggesting a hypoxic state. [16][17] A functional consequence of tissue hypoxia is the stabilization of a family of oxygen-labile transcription factors called hypoxiainducing factors (HIFs). HIFs are heterodimers of an O 2 -labile ␣-subunit, and a stable ␤-subunit called the aryl hydrocarbon receptor nuclear translocator (ARNT). Once the HIF-␣:ARNT complex is formed, it can then translocate to the nucleus and activate the transcription of genes containing hypoxia-responsive elements. Hematopoietic cells, including HSCs, express HIF-1␣ mRNA. 18 In hypoxic conditions with an oxygen concentration below 2%, the HIF-␣ protein is stable and the complex with ARNT is formed, translocates to the nucleus, and initiates transcription of hypoxia-responsive elemen...