Cardiac-Specific Overexpression of HIF-1α Prevents Deterioration of Glycolytic Pathway and Cardiac Remodeling in Streptozotocin-Induced Diabetic Mice

Xue, Wanli; Cai, Lu; Tan, Yi; Thistlethwaite, Patricia A.; Kang, Y. James; Li, Xiaokun; Feng, Wenke

doi:10.2353/ajpath.2010.091091

Cited by 52 publications

(36 citation statements)

References 44 publications

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“…In addition, HDAC5 knockout mice developed cardiac hypertrophy, which may be a consequence of deregulated developmental adaptation to cardiac hypoxia. 54 Transgenic overexpression of HIF-1a attenuated the cardiac hypertrophy caused by HDAC5 knockout, 68 proving a functional interplay between HDAC5 and HIF-1 with a genetic approach.…”

Section: Discussionmentioning

confidence: 99%

AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol

et al. 2015

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Hypoxia-inducible factor 1 (HIF-1) transcriptionally promotes production of adenosine triphosphate (ATP) whereas AMPK senses and regulates cellular energy homeostasis. A histone deacetylase (HDAC) activity has been proven to be critical for HIF-1 activation but the underlying mechanism and its role in energy homesostasis remain unclear. Here, we demonstrate that HIF-1 activation depends on a cytosolic, enzymatically active HDAC5. HDAC5 knockdown impairs hypoxia-induced HIF-1a accumulation and HIF-1 transactivation, whereas HDAC5 overexpression enhances HIF-1a stabilization and nuclear translocation. Mechanistically, we show that Hsp70 is a cytosolic substrate of HDAC5; and hyperacetylation renders Hsp70 higher affinity for HIF-1a binding, which correlates with accelerated degradation and attenuated nuclear accumulation of HIF-1a. Physiologically, AMPK-triggered cytosolic shuttling of HDAC5 is critical; inhibition of either AMPK or HDAC5 impairs HIF-1a nuclear accumulation under hypoxia or low glucose conditions. Finally, we show specifically suppressing HDAC5 is sufficient to inhibit tumor cell proliferation under hypoxic conditions. Our data delineate a novel link between AMPK, the energy sensor, and HIF-1, the major driver of ATP production, indicating that specifically inhibiting HDAC5 may selectively suppress the survival and proliferation of hypoxic tumor cells.

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Section: Discussionmentioning

confidence: 99%

AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol

et al. 2015

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“…As mentioned above, endothelial dysfunction in diabetes is related to impairment of hypoxia-induced production of eNOS, SDF-1, CXCR4 and VEGF. This impairment can presumably be ascribed to destabilisation of HIF-1α, since overexpression of Hif-1α normalises VEGF levels, improves development of myocardial capillary network and inhibits cardiomyocyte hypertrophy and cardiac fibrosis following myocardial injury [85]. In addition, increased expression or stabilisation of HIF-1α is critical to improve wound healing [59,63,68] and it enhances the vascular response to critical limb ischaemia in diabetic mice.…”

Section: Impairment Of Hif-1 Regulation In Diabetesmentioning

confidence: 99%

Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes

2011

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Diabetes is frequently associated with hypoxia and is known to impair ischaemia-induced neovascularisation and other forms of adaptive cell and tissue responses to low oxygen levels. Hyperglycaemia appears to be the driving force of such deregulation. Recent data indicate that destabilisation of hypoxia-inducible factor 1 (HIF-1) is most likely the event that transduces hyperglycaemia into the loss of the cellular response to hypoxia in most diabetic complications. HIF-1 is a critical transcription factor involved in oxygen homeostasis that regulates a variety of adaptive responses to hypoxia, including angiogenesis, metabolic reprogramming and survival. Thus, destabilisation of HIF-1 is likely to have a negative impact on cell and tissue adaptation to low oxygen. Indeed, destabilisation of HIF-1 by high glucose levels has serious consequences in various organs and tissues, including myocardial collateralisation, wound healing, renal, neural and retinal function, as a result of poor cell and tissue responses to low oxygen. This review aims to integrate and summarise some of the most recent developments, including new proposed molecular models, on this research topic, particularly in terms of their implications for potential therapeutic approaches for the prevention or treatment of some of the diabetic complications characterised by impaired cellular and tissue responses to hypoxia.

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“…These responses involve up to 200 genes for angiogenesis, erythropoiesis, antiapoptosis, free radical production/scavenging, necrosis and stem cell differentiation [44]. Cellular PC through HIF upregulation has been extensively investigated in the neonate model of hypoxia/ ischemia [42], but is also being examined in the heart [45,46], brain [47], kidney [48] and liver [49]. …”

Section: Anoxia Tolerance and Ischemic Pc Share Common Mechanismsmentioning

confidence: 99%

Alleviating Brain Stress: What Alternative Animal Models Have Revealed About Therapeutic Targets For Hypoxia and Anoxia

Milton

2013

Future Neurol.

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While the mammalian brain is highly dependent on oxygen, and can withstand only a few minutes without air, there are both vertebrate and invertebrate examples of anoxia tolerance. One example is the freshwater turtle, which can withstand days without oxygen, thus providing a vertebrate model with which to examine the physiology of anoxia tolerance without the pathology seen in mammalian ischemia/reperfusion studies. Insect models such as Drosophila melanogaster have additional advantages, such as short lifespans, low cost and well-described genetics. These models of anoxia tolerance share two common themes that enable survival without oxygen: entrance into a state of deep hypometabolism, and the suppression of cellular injury during anoxia and upon restoration of oxygen. The study of such models of anoxia tolerance, adapted through millions of years of evolution, may thus suggest protective pathways that could serve as therapeutic targets for diseases characterized by oxygen deprivation and ischemic/reperfusion injuries.

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Cardiac-Specific Overexpression of HIF-1α Prevents Deterioration of Glycolytic Pathway and Cardiac Remodeling in Streptozotocin-Induced Diabetic Mice

Cited by 52 publications

References 44 publications

AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol

AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1α and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol

Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes

Alleviating Brain Stress: What Alternative Animal Models Have Revealed About Therapeutic Targets For Hypoxia and Anoxia

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