Mechanistic analysis demonstrated that celastramycin reduced the protein levels of HIF-1α (hypoxia-inducible factor 1α), which impairs aerobic metabolism, and κB (nuclear factor-κB), which induces proinflammatory signals, in PAH-PASMCs, leading to reduced secretion of inflammatory cytokine.
Hypoxia-inducible factor-1-α (HIF 1α) is a pro-proliferative mediator and may be involved in the development of human pulmonary arterial hypertension .
Our in vitro results showed that inhibition of Src (Tyr416) phosphorylation repressed PAH-PASMC proliferation and migration by inhibiting hypoxia-inducible factor-1α (HIF-1α) expression through Akt/mTOR signal pathway.
We hypothesized that a βAR-active conformation (R**) that leads to HIF-1 is separable from the cAMP-activating conformation (R*) and that pulmonary arterial hypertension (PAH) patients with HIF-biased conformations would not respond to a cAMP agonist.
Overall, our data suggest that HIF-1α is regarded as an alternative target for CAPE in addition to NF-κB, and may represent a promising therapeutic agent for the treatment of PAH diseases.
This study provides mechanistic insights into hypoxic reprogramming that permits vascular remodeling, and thus provides proof of concept for anti-remodeling therapy for PAH through direct modulation of CD146-HIF-1α cross-regulation.
TPT ameliorates the hypoxia-induced pulmonary vascular remodeling in PAH, and the mechanism is associated with TPT-mediated inhibition of hypoxia-induced upregulation of HIF-1α and TRPC1/4/6 expression, Ca<sup>2+</sup> influx, and PASMCs proliferation.
Altogether, our findings indicate that miR-150 may exert inhibitory effects on excessive proliferation and migration of PASMCs through down-regulation of HIF-1α, providing new insights into the potential mechanisms of human PAH.
In conclusion, the mechanism of mitoKATP regulating the HIF-1α/miR-210/ISCU signaling axis and formation of a positive feedback loop exists in the PAH rat model.
The following mutually reinforcing, mitochondrial abnormalities favor proliferation, impair apoptosis, and are relatively restricted to PAH and cancer cells: (1) Epigenetic silencing of superoxide dismutase-2 (SOD2) by methylation of CpG islands creates a pseudohypoxic redox environment that causes normoxic activation of hypoxia inducible factor (HIF-1α).
Using in vitro gain- and loss-of-function approaches, we mechanistically demonstrate that miR-204 diminution promotes RUNX2 up-regulation and that sustained RUNX2 expression activates hypoxia-inducible factor-1α, leading to aberrant proliferation, resistance to apoptosis, and subsequent transdifferentiation of PAH-PASMCs into osteoblast-like cells.
These findings suggested that the mitogen‑activated protein kinase and PI3K/Akt signaling pathways, and HIF‑1 may perform a specific function in the pathogenesis of PAH.
In addition, combined HIF-1α and homogeneous EPC therapy was more effective at attenuating PAH and increasing the density of pulmonary small arteries, compared with EPC transplantation alone.
Furthermore, using a gain and loss of function approach, we showed that increased hypoxia-inducible factor 1α, which is observed in PAH, triggers this decrease in miR-223 expression and subsequent overexpression of PARP-1 allowing PAH-PASMC proliferation and resistance to apoptosis.
We also showed that PARP-1 activation accounts for miR-204 downregulation (quantitative reverse transcription polymerase chain reaction) and the subsequent activation of the transcription factors nuclear factor of activated T cells and hypoxia-inducible factor 1-α in PAH-PASMCs, previously shown to be critical for PAH in several models.
In summary, these findings indicate that viral protein induced oxidative stress results in HIF-1α dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH.
These findings indicate that alterations of nitric oxide and MnSOD contribute to pathological HIF-1alpha expression and account for lower numbers of mitochondria in IPAH-ECs.
Mitochondrial abnormalities that disturb the ROS-HIF-1alpha-Kv1.5 O(2)-sensing pathway contribute to the pathogenesis of PAH and cancer and constitute promising therapeutic targets.
DHEA decreases HIF-1alpha accumulation under hypoxia in human pulmonary artery cells: potential role in the treatment of pulmonary arterial hypertension.