HIF2α regulates the synthesis and release of epinephrine in the adrenal medulla

Watts, Deepika; Bechmann, Nicole; Meneses, Ana; Poutakidou, Ioanna K.; Kaden, Denise; Conrad, Catleen; Krüger, Anja; Stein, Johanna; El‐Armouche, Ali; Chavakis, Triantafyllos; Eisenhofer, Graeme; Peitzsch, Mirko; Wielockx, Ben

doi:10.1007/s00109-021-02121-y

Cited by 10 publications

(8 citation statements)

References 61 publications

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“…At the physiological level, studies in mice models have shown that HIF2α has prominent functions in the development of the CB and its responsiveness to acute hypoxia [ 6 , 7 , 8 ]. It is also essential for the growth, differentiation, and function of the sympathoadrenal lineage [ 9 , 10 , 11 , 12 ]. However, the roles of HIF1α and HIF2α in HNPGL and PPGL development have been more poorly defined.…”

Section: Introductionmentioning

confidence: 99%

Differential HIF2α Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions

Celada

Cubiella

San-Juan-Guardado

et al. 2022

Cancers

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Hypoxia-inducible factors (HIF) 2α and 1α are the major oxygen-sensing molecules in eukaryotic cells. HIF2α has been pathogenically linked to paraganglioma and pheochromocytoma (PPGL) arising in sympathetic paraganglia or the adrenal medulla (AM), respectively. However, its involvement in the pathogenesis of paraganglioma arising in the carotid body (CB) or other parasympathetic ganglia in the head and neck (HNPGL) remains to be defined. Here, we retrospectively analyzed HIF2α by immunohistochemistry in 62 PPGL/HNPGL and human CB and AM, and comprehensively evaluated the HIF-related transcriptome of 202 published PPGL/HNPGL. We report that HIF2α is barely detected in the AM, but accumulates at high levels in PPGL, mostly (but not exclusively) in those with loss-of-function mutations in VHL and genes encoding components of the succinate dehydrogenase (SDH) complex. This is associated with upregulation of EPAS1 and the HIF2α-regulated genes COX4I2 and ADORA2A. In contrast, HIF2α and HIF2α-regulated genes are highly expressed in CB and HNPGL, irrespective of VHL and SDH dysfunctions. We also found that HIF2α and HIF1α protein expressions are not correlated in PPGL nor HNPGL. In addition, HIF1α-target genes are almost exclusively overexpressed in VHL-mutated HNPGL/PPGL. Collectively, the data suggest that involvement of HIF2α in the physiology and tumor pathology of human paraganglia is organ-of-origin-dependent and HIF1α-independent.

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Section: Introductionmentioning

confidence: 99%

Differential HIF2α Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions

Celada

Cubiella

San-Juan-Guardado

et al. 2022

Cancers

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“…Increased chromogranin A expression has also been reported in patients with type 1 diabetes [ 77 ] and it correlates with increased plasma catecholamine levels during the early stages of diabetes [ 78 , 79 ]. As HIF-2α regulates expression of catecholamine biosynthetic enzymes in adrenal chromaffin cells [ 80 – 82 ], we analyzed the expression of HIF-2α in adrenal glands. The levels of HIF-2α protein were highly variable in Hif1aCKO, with undetectable expression in two samples from diabetic and one sample from non-diabetic Hif1aCKO (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy

Hrabalova

Bohuslavová

Matejkova

et al. 2023

Cardiovasc Diabetol

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Background An altered sympathetic nervous system is implicated in many cardiac pathologies, ranging from sudden infant death syndrome to common diseases of adulthood such as hypertension, myocardial ischemia, cardiac arrhythmias, myocardial infarction, and heart failure. Although the mechanisms responsible for disruption of this well-organized system are the subject of intensive investigations, the exact processes controlling the cardiac sympathetic nervous system are still not fully understood. A conditional knockout of the Hif1a gene was reported to affect the development of sympathetic ganglia and sympathetic innervation of the heart. This study characterized how the combination of HIF-1α deficiency and streptozotocin (STZ)-induced diabetes affects the cardiac sympathetic nervous system and heart function of adult animals. Methods Molecular characteristics of Hif1a deficient sympathetic neurons were identified by RNA sequencing. Diabetes was induced in Hif1a knockout and control mice by low doses of STZ treatment. Heart function was assessed by echocardiography. Mechanisms involved in adverse structural remodeling of the myocardium, i.e. advanced glycation end products, fibrosis, cell death, and inflammation, was assessed by immunohistological analyses. Results We demonstrated that the deletion of Hif1a alters the transcriptome of sympathetic neurons, and that diabetic mice with the Hif1a-deficient sympathetic system have significant systolic dysfunction, worsened cardiac sympathetic innervation, and structural remodeling of the myocardium. Conclusions We provide evidence that the combination of diabetes and the Hif1a deficient sympathetic nervous system results in compromised cardiac performance and accelerated adverse myocardial remodeling, associated with the progression of diabetic cardiomyopathy.

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“…A previous report claimed no association of PD‐L1 expression and HIF in PPGL [ 30 ]. However, that study analyzed HIF1α as a pseudohypoxia biomarker that, in contrast to HIF2α, does not distinguish between SDH ‐mutated and SDH ‐wild‐type tumors [ 32 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype

Celada

Cubiella

San-Juan-Guardado

et al. 2022

The Journal of Pathology

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Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia‐inducible factor 2 (HIF2)‐mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death‐ligand 1 (PD‐L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD‐L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD‐L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD‐L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD‐L1 and CD8 expression was lower in norepinephrine than epinephrine‐secreting PPGL. This in silico analysis also revealed the low PD‐L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α‐coding gene, EPAS1, which, together with SDH‐mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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HIF2α regulates the synthesis and release of epinephrine in the adrenal medulla

Cited by 10 publications

References 61 publications

Differential HIF2α Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions

Differential HIF2α Protein Expression in Human Carotid Body and Adrenal Medulla under Physiologic and Tumorigenic Conditions

Dysregulation of hypoxia-inducible factor 1α in the sympathetic nervous system accelerates diabetic cardiomyopathy

Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype

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