LC3 as a potential therapeutic target in hypoxia-induced pulmonary hypertension

Abstract

Recent research suggests that microtubule-associated protein 1 light chain 3B (LC3B) confers protection against hypoxia-induced pulmonary hypertension (HPH) by inhibiting proliferation of pulmonary artery (PA) wall cells. We recently demonstrated that 17β-estradiol (E2), a sex hormone with known protective properties in HPH, increases lung LC3-II expression in chronically hypoxic male Sprague-Dawley rats. Stimulatory E2 effects on LC3-II were recapitulated in isolated hypoxic (1% O 2 for 48 h), but not room air-exposed primary rat PA endothelial cells (PAECs), and were accompanied by hypoxia-specific inhibitory effects on other parameters involved in proproliferative signaling (MAPK3/ERK1-MAPK1/ERK2 activation, VEGF secretion), as well as inhibitory effects on PAEC proliferation. Taken together, these results suggest that E2 mediates hypoxia-specific antiproliferative effects in PAECs, and that stimulation of autophagy may be one of the underlying mechanisms of E2-mediated protection in HPH. Viewed in the context of previously published data, these results indicate that LC3 1) exerts protective effects in the pathogenesis of HPH, and 2) may represent a potential target for future therapeutic interventions in HPH.

Keywords: 17-beta estradiol; MAPK1/ERK2; MAPK3/ERK1; cell proliferation; estrogen; hypoxia; pulmonary artery endothelial cells; pulmonary vascular remodeling.

Figure 1. Potential role of autophagy in attenuation of hypoxia-induced pulmonary hypertension (HPH). Lack of increase or insufficient increase in LC3 in HPH may allow for pulmonary artery endothelial cell (PAEC) activation and proliferation with subsequent hypoxic pulmonary vascular remodeling. PAECs play a critical role in HPH development by secreting growth factors and pro-inflammatory cytokines that further stimulate PA smooth muscle cell proliferation and recruitment of inflammatory as well as progenitor cells. Hypoxia-specific stimulatory effects of 17β-estradiol (E2) on autophagy may attenuate PAEC activation and proliferation, thereby contributing to attenuated hypoxic pulmonary vascular remodeling. Note that, in addition to autophagy of PAECs, autophagy of PA smooth muscle cells may also represent a therapeutic target in HPH. Similar effects may be observed with other inducers of autophagy (e.g., rapamycin).