Vasohibin1, a new IRES trans-acting factor for induction of (lymph)angiogenic factors in early hypoxia

Abstract

Hypoxia, a major inducer of angiogenesis, is known to trigger major changes of gene expression at the transcriptional level. Furthermore, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 cardiomyocytes: most genes are not induced at the transcriptome-, but at the translatome level, including all IRES-containing mRNAs. Our data reveal sequential activation of (lymph)angiogenic mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) able to activate the earliest induced FGF1 IRES while it inhibits the other IRESs. Thus this new ITAF may have opposite effects on IRES activities in the steps of early hypoxia. These data suggest that IRESome composition varies at different stages of hypoxia, leading to sequential induction of (lymph)angiogenic factors required to form new functional vessels in ischemic heart.

IRES Trans-Acting Factors, Key Actors of the Stress Response

“…This problem has been circumvented by using another reporter gene such as beta-galactosidase [52]. Mutating the cryptic splicing sites in the LucR gene is also a good solution [72]. Stringent and carefully controlled experiments such as Northern blots, RT qPCR or first cistron knockdown have been necessary to demonstrate the presence of bona fide cellular IRESs [49,51,53,58].…”

“…In particular, chronic heart failure is a public health issue. IRES-dependent translation plays a major role during ischemia: a very recent mid-scale study shows that, unexpectedly, the expression of most (lymph)angiogenic factors is not induced at the transcriptome level but at the translatome level in hypoxic cardiomyocytes [72]. The same study indicates that the IRESs of (lymph)angiogenic factors mRNAs, FGF1, FGF2, VEFGA, VEGFC and VEGFD are activated in early hypoxia, while non angiogenic IRESs such as EMCV or c- myc IRES are activated in late hypoxia.…”

“…The regulation of the (lymph)angiogenic growth factor expression during hypoxia: (Lymph)angiogenic growth factors are regulated at the transcriptional and/or translational levels during hypoxia. In conditions of tumoral hypoxia, the regulation is both transcriptional and translational through the internal ribosome entry site (IRES)-dependent mechanism, whereas during cardiac ischemia in hypoxic cardiomyocytes, most regulation is translational [72]. The IRESs of (lymph)angiogenic growth factor mRNAs are activated during early hypoxia by an HIF1-independent mechanism.…”

Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy Development

“…However, hypoxia also constitutes major stress in other pathologies, such as ischemic pathologies, in which artery occlusion leads to hypoxic conditions, and then angiogenesis is promoted as a cellular response to fight the lack of oxygen and nutrients in cells. It has been shown that (lymph)angiogenesis is also induced by hypoxia and mediated at both transcriptional and post-transcriptional levels [ 90 , 91 ]. VEGF-A and FGF2, major angiogenic factors, and the lymphangiogenic growth factor VEGF-C are all induced by hypoxia through a translational mechanism [ 90 ].…”

“…VEGF-A and FGF2, major angiogenic factors, and the lymphangiogenic growth factor VEGF-C are all induced by hypoxia through a translational mechanism [ 90 ]. As we have already mentioned above, several IRESs have been identified in the mRNAs of (lymph)angiogenic growth factors from the FGF and VEGF families, suggesting that the activation of angiogenesis and lymphangiogenesis during stress might be highly controlled via IRES-mediated translation [ 91 ]. VEGF-A has pro-lymphangiogenic properties and its induction under hypoxia occurs in both physiological states and pathological conditions, such as ischemia or tumour development [ 92 ].…”