Commentary: The apolipoprotein A-I mimetic peptide, D-4F, restrains neointimal formation through heme oxygenase-1 up-regulation.

We read with great interest the work of Liu et al. (2017b) showing that D-4F inhibited vascular smooth muscle cells (VSMC) proliferation and migration in vitro and neointimal formation in vivo through heme oxygenase-1(HO-1) up-regulation. Authors' conclusions further demonstrate that HO-1 represents a druggable target for vascular injury prevention and that D-4F may be exploited as a safe and effective treatment to induce HO-1 into a clinical setting. In fact, previous reports showed that a single dose of D-4F is safe and well tolerated in patients with coronary heart disease (Bloedon et al., 2008; Sherman et al., 2010). Furthermore, D-4F, besides being an inducer of HO-1, exhibited pleiotropic effects contributing to vascular homeostasis such as antioxidant and anti-inflammatory effects (Kruger et al., 2005; Rosenbaum et al., 2015; Liu et al., 2017a). Interestingly, all these effects are consistent with HO-1 biological functions. In particular, HO-1 may be expressed under basal conditions (Maines et al., 1986; Bauer et al., 1998) and it is induced by different compounds and stress-related stimuli (Li Volti et al., 2008; Bramanti et al., 2012; Barbagallo et al., 2013). In addition, a number of natural antioxidant compounds contained in foods and plants have been demonstrated to be effective non-stressful and non-cytotoxic inducers of the response protein HO-1 in various cellular models. Most of these compounds are contained in plants, which besides having been widely used as food, spices, or flavoring also represent locally traditional medicinal plants. However, such compounds have intrinsic antioxidant and anti-inflammatory effects because of their ability to induce antioxidant responsive elements (ARE) which are responsible for cellular homeostasis maintenance; on the other hand, D-4F has specific activity on HO-1 induction. Finally, one more aspects deserves to be pointed out referring to the interesting work of Liu et al. Noteworthy, the biological effects of HO-1 have been shown to be cell specific. In fact, several lines of evidence are consistent with the authors' conclusion regarding the effect of HO-1 on VSMC proliferation and migration in vitro (Li Volti et al., 2002; Durante, 2010). On the other hand, HO-1 induction results in a significant increase of endothelial cell proliferation (Li Volti et al., 2002, 2005). Such particular cell specificity is of great clinical interest in the case of vascular injury and neointima formation since this process is characterized by increased VSMC proliferation with a reduction of endothelial formation. To this regard, Duckers et al. (2001) showed that HO-1 reduced the proliferative response to vascular injury in vivo and reduced VSMC proliferation in vivo via p21 regulation. Taken all together, the work of Liu et al. provide a significant pharmacological tool to exploit HO-1 beneficial effects into a clinical setting with particular regard to restenosis.

Author contributions

GL, RA, and DT reviewed scientific literature and contributed to the writing of this article.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.