Therapeutic implication of Sonic Hedgehog as a potential modulator in ischemic injury

Sonic Hedgehog (SHh) is a homology protein that is involved in the modeling and development of embryonic tissues. As SHh plays both protective and harmful roles in ischemia, any disruption in the transduction and regulation of the SHh signaling pathway causes ischemia to worsen. The SHh signal activation occurs when SHh binds to the receptor complex of Ptc-mediated Smoothened (Smo) (Ptc-smo), which initiates the downstream signaling cascade. This article will shed light on how pharmacological modifications to the SHh signaling pathway transduction mechanism alter ischemic conditions via canonical and non-canonical pathways by activating certain downstream signaling cascades with respect to protein kinase pathways, angiogenic cytokines, inflammatory mediators, oxidative parameters, and apoptotic pathways. The canonical pathway includes direct activation of interleukins (ILs), angiogenic cytokines like hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and hypoxia-inducible factor alpha (HIF-), which modulate ischemia. The non-canonical pathway includes indirect activation of certain pathways like mTOR, PI3K/Akt, MAPK, RhoA/ROCK, Wnt/-catenin, NOTCH, Forkhead box protein (FOXF), Toll-like receptors (TLR), oxidative parameters such as GSH, SOD, and CAT, and some apoptotic parameters such as Bcl2. This review provides comprehensive insights that contribute to our knowledge of how SHh impacts the progression and outcomes of ischemic injuries.