Content area
Full Text
Introduction
Diabetes mellitus (DM) is a major risk factor for ischemic and hemorrhagic stroke. Stroke patients with DM exhibit a worse neurovascular prognosis and white-matter (WM) lesion and neurological function than non-DM stroke patients. Therefore, development of therapeutic approaches for the DM-stroke population are urgently needed.
Type-2 diabetes (T2DM) constitutes 90% of the DM population. DM patients have low levels of blood high-density lipoprotein (HDL) (Maron, 2000; Sharrett et al., 2001; Gotto and Brinton, 2004; Bonora, 2006) and impairment of HDL function such as the antioxidative capacity of HDL (Bonora, 2006; Kontush and Chapman, 2006; Anan et al., 2010; Kruit et al., 2010; Mulder et al., 2011; Scheffer et al., 2011; Dullaart et al., 2012). Improved HDL functionality may contribute to maintenance of pancreas beta-cell function in subjects with well-controlled T2DM (Dullaart et al., 2012). Impairment of HDL anti-oxidative function in T2DM contributes to enhanced formation of oxidative stress products, such as advanced glycation end products (AGEs) (Mulder et al., 2011; Scheffer et al., 2011). Dysfunction of HDL also promotes inflammatory effects (Kruit et al., 2010) and increases proinflammatory factor activation, such as tumor necrosis factor alpha (TNFα) (Igarashi et al., 2008; Nayak et al., 2010; Gomez-Banoy et al., 2016), high-mobility group box 1 (HMGB1) and AGE receptor (RAGE) (Williams and Nadler, 2007; Ye et al., 2011), and plasminogen activator inhibitor-1 (PAI-1) (Scarabin et al., 1998; Bonora, 2006; Williams and Nadler, 2007; Al-Hamodi et al., 2011; Ye et al., 2011; Costa and Soares, 2013; Gorska-Ciebiada et al., 2016), which can exacerbate vascular and WM damage after stroke in T2DM. Therefore, improving HDL function through modification of its lipid and/or protein content maybe a therapeutic target for the treatment of stroke in T2DM.
In human, the circulating blood contains only about 40% of the total amount of HDL, with most of HDL particles present in human interstitial fluids including the arterial intimal fluid (Miller et al., 2013). The HDL particles in plasma contain either a single copy or multiple copies of apolipoprotein A-I (ApoA-I). ApoA-I has been shown to possess several atheroprotective functions, including inhibition of inflammation. However, ApoA-I is a selective target for oxidation by myeloperoxidase, which results in impaired HDL function (Imaizumi et al., 2011). 4F is an economical 18 amino acid peptide mimetic...