4.1 HIF-1 signaling pathway
“HIF-1 signaling” is a major regulator of the hypoxia signaling
pathway, leading to similar biochemical and physical reactions,
including oxygen sensing, increasing oxygen delivery and reducing oxygen
consumption (Zhu et al. 2013).
(1) Oxygen sensor
In recent years, the relationship between several oxygen sensors and
hypoxia in some fishes has been elucidated
(Geng et al. 2014;
Wang et al. 2015). We found that
the transcriptional expressions of the oxygen sensors (FIH-1, PHD2, and
PHD3) were significantly upregulated and their regulating miRNAs were
significantly downregulated (Table 1 ), which indicates that
oxygen sensors and their regulation of miRNAs play an vital role in
response to hypoxia. Similar results were found in P. vachelliliver and brain(Guosong et al.2017).
(2) Increase oxygen delivery
The pattern of gene upregulation (19/23) in the “VEGF signaling
pathway” may be involved in promoting their vasopermeability,
angiogenesis (VEGF, KDR1, ANGPTL4, up-regulated) and mediating the
vascular tone (NOS2, ECE1, up-regulated) (Table 1 ). Similar
activation of the VEGF or ANGPTL4 has been shown in P. vachelliliver and Astronotus ocellatus(Baptista et al. 2016;
Zhang et al. 2016b).
It has been widely accepted that many
blood
regulations in fishes contribute to improve oxygen uptake and transport
to tissues in low oxygen environments. In P. vachelli similar
raised blood indices (RBC, HB and SI/TIBC) and liver mRNA levels (TFRC,
CA and EPO) have been reported (Guosonget al. 2017). However, in this study “African trypanosomiasis”
was enriched by a downregulated anemia related gene. We found that the
genes or proteins involved in heme synthesis (ALAS2, HRG-1A, urod,
Blvra, UGT2A1, PPOX, HMOX2) and erythropoiesis (TF, TFRC, CA, HBα,
PC-7236-HBβ) were significantly reduced (Table 1 and Fig. 5 ).
This may be because the muscle tissue is not the hematopoietic organ of
the fish. However, among the more highly upregulated proteins in theD. rerio muscle during hypoxia were two variants of HBα, which
may be due to different period and level of hypoxia or various
regulatory mechanism in different fish muscle
(Chen et al. 2013a).
(3) Reduce oxygen consumption
In this study, upregulation of GLUT1 (HIF-1α target gene) suggested a
promotion in anaerobic metabolism in muscle, similar to previously
reported results in P. vachelli liver
(Zhang et al. 2016b).
Furthermore,
upregulated PDK1, which is member of HIF-1α target gene, acts to
suppress PDHA, involved in inhibiting the initiation of the “TCA
cycle”. The downregulation of all rate-limiting enzymes of the “TCA
cycle” (CS, IDH, DLD, miR-193b/457a/15b-OGDH, miR-210/338-SDHb, SDHa,
miR-457a/214-MDH1) indicates an inhibition of aerobic metabolism
(Table 1 and Fig. 5 ) (Cerretelli&
Gelfi 2011).
Surprisingly, both the rate-limiting enzymes (PK, miR-181a/-338-HK1,
HK2, PFK1) of “Glycolysis/Gluconeogenesis” and LDH were significantly
downregulated (Table 1 and Fig. 5 ), contrary to the accepted
metabolic model of hypoxic stress. Such lower level for anaerobic
glycolysis was found at both transcriptional and protein levels inP. vachelli muscle induced by hypoxia. However, these results
were different from that of other fishes. For example, hypoxia increased
glycolysis-related enzyme activities and LDH
in the P. vachelli liver andD. rerio muscle, respectively (Chenet al. 2013a). It may be that the muscles in our treatment
undergo more severe hypoxia, resulting in a cellular metabolic disorder.