Abstract
The hypoxic response is a stress response triggered by low oxygen tension. Hypoxia-inducible factors (HIFs) play a prominent role in the pathobiology of hypoxia-associated conditions, including pulmonary hypertension (PH) and polycythemia. The c-Jun N-terminal protein kinase (JNK), a stress-activated protein kinase that consists of two ubiquitously expressed isoforms, JNK1 and JNK2, and a tissue-specific isoform, JNK3, has been shown to be activated by hypoxia. However, the physiological role of JNK1 and JNK2 in the hypoxic response remains elusive. Here, using genetic knockout cells and/or mice, we show that JNK2, but not JNK1, up-regulates the expression of HIF-1α and HIF-2α and contributes to hypoxia-induced PH and polycythemia. Knockout or silencing of JNK2, but not JNK1, prevented the accumulation of HIF-1α in hypoxia-treated cells. Loss of JNK2 resulted in a decrease in HIF-1α and HIF-2α mRNA levels under resting conditions and in response to hypoxia. Consequently, hypoxia-treated Jnk2-/- mice had reduced erythropoiesis and were less prone to polycythemia because of decreased expression of the HIF target gene erythropoietin (Epo). Jnk2-/- mice were also protected from hypoxia-induced PH, as indicated by lower right ventricular systolic pressure, a process that depends on HIF. Taken together, our results suggest that JNK2 is a positive regulator of HIFs and therefore may contribute to HIF-dependent pathologies.
Highlights
The last 2 decades have brought insight into the mechanisms of hypoxia-associated diseases, including pulmonary hypertension (PH)2 and polycythemia, primarily through the discovery and under
We show that JNK2, but not JNK1, positively regulates Hypoxia-inducible factors (HIFs) in a murine model of ambient hypoxia and thereby contributes to hypoxia-induced PH and polycythemia
Our data suggest that JNK2, but not JNK1, positively regulates HIF-1␣, which is in line with recent studies by our group and others that JNK1 and JNK2 have shared and distinct functions [25, 32]
Summary
It is known that both HIF-1␣ and HIF-2␣ proteins are constitutively degraded by the ubiquitin-proteasome system in oxygen-replete states but stabilized under conditions of low oxygen tension [31]. Hypoxia treatment induced de novo erythropoiesis in the bone marrow of wild-type mice, as shown by increased numbers in total erythroid cells as well as in the subpopulations of proerythroblasts and early erythroblasts (Fig. 7, D and E). Under hypoxic conditions, Jnk2Ϫ/Ϫ mice exhibited less de novo erythropoiesis compared with wild-type mice, as shown by reduced numbers of total erythroid cells and subpopulations of proerythroblasts and early and late erythroblasts (Fig. 7, D and E) Taken together, these data suggest that JNK2 contributes to de novo erythropoiesis in response to hypoxia, both medullary and extramedullary. These data suggest that JNK2 deficiency protects mice from chronic hypoxia-induced PH, consistent with its role in HIF regulation
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