A novel nitroalkene‐α‐tocopherol analogue inhibits inflammation and ameliorates atherosclerosis in Apo E knockout mice

Abstract

Background and purpose Atherosclerosis is characterized by chronic low‐grade inflammation with concomitant lipid accumulation in the arterial wall. Anti‐inflammatory and anti‐atherogenic properties have been described for a novel class of endogenous nitroalkenes (nitrated‐unsaturated fatty acids), formed during inflammation and digestion/absorption processes. The lipid‐associated antioxidant α‐tocopherol is transported systemically by LDL particles including to the atheroma lesions. To capitalize on the overlapping and complementary salutary properties of endogenous nitroalkenes and α‐tocopherol, we designed and synthesized a novel nitroalkene‐α‐tocopherol analogue (NATOH) to address chronic inflammation and atherosclerosis, particularly at the lesion sites. Experimental approach We synthesized NATOH, determined its electrophilicity and antioxidant capacity and studied its effects over pro‐inflammatory and cytoprotective pathways in macrophages in vitro. Moreover, we demonstrated its incorporation into lipoproteins and tissue both in vitro and in vivo, and determined its effect on atherosclerosis and inflammatory responses in vivo using the Apo E knockout mice model. Key results NATOH exhibited similar antioxidant capacity to α‐tocopherol and, due to the presence of the nitroalkenyl group, like endogenous nitroalkenes, it exerted electrophilic reactivity. NATOH was incorporated in vivo into the VLDL/LDL lipoproteins particles to reach the atheroma lesions. Furthermore, oral administration of NATOH down‐regulated NF‐κB‐dependent expression of pro‐inflammatory markers (including IL‐1β and adhesion molecules) and ameliorated atherosclerosis in Apo E knockout mice. Conclusions and implications In toto, the data demonstrate a novel pharmacological strategy for the prevention of atherosclerosis based on a creative, natural and safe drug delivery system of a non‐conventional anti‐inflammatory compound (NATOH) with significant potential for clinical application.

A novel nitroalkene vitamin E analogue inhibits the NLRP3 inflammasome and protects against inflammation and glucose intolerance triggered by obesity

“…We have previously demonstrated that a rationally designed nitroalkene derived from a natural and safe drug delivery system (e.g. α-tocopherol or Vitamin E), was a novel and thriving pharmacological strategy for the treatment of atherosclerosis [ 47 ]. This strategy, which was named NATOH (5-nitroethenyl-γ-tocopherol) and was specifically designed to be carried by the VLDL/LDL system to atheroma lesions by homologizing the α-tocopherol structure, probed to work as a non-conventional anti-inflammatory compound in vitro and in vivo .…”

“…This strategy, which was named NATOH (5-nitroethenyl-γ-tocopherol) and was specifically designed to be carried by the VLDL/LDL system to atheroma lesions by homologizing the α-tocopherol structure, probed to work as a non-conventional anti-inflammatory compound in vitro and in vivo . Moreover, NATOH was able to decrease the atherosclerotic plaque formation and to inhibit the expression of relevant cytokines and adhesion molecules liberated at the lesions site in an atherosclerosis mouse model (ApoE knock out mice) [ 47 ]. In this work, we show that a novel and hydro soluble derivative of NATOH, named NATx0, previously described by our group [ 48 ], has promissory beneficial effects over inflammatory processes occurring during obesity, glucose intolerance and type II diabetes.…”

“…Recently, our group described a novel pharmacological strategy for the treatment of atherosclerosis, based on the design and development of a nitroalkene-α-tocopherol derivative (NATOH) [ 47 ]. Mice treated with NATOH showed down-regulation of NF-kB-dependent pro-inflammatory markers (including IL-1β and adhesion molecules) and amelioration of atherosclerosis.…”

A Nitroalkene Benzoic Acid Derivative Targets Reactive Microglia and Prolongs Survival in an Inherited Model of ALS via NF-κB Inhibition

“…Endogenous electrophilic nitroalkene fatty acids are known to target different signaling pathways including Nrf2 and NF-κB [18][19][20]. Recently, we reported the synthesis, physicochemical characterization, and therapeutic effects of nitroalkene-tocopherol analog compounds [21,22], laying the foundation for the rational design of novel nonconventional anti-inflammatory compounds. The addition of an electrophilic nitroalkene moiety to the tocopherol scaffold confers the hybrid compound with multifaceted therapeutical activity in a model of atherosclerosis through combined inhibition of NF-κB signaling and activation of Nrf2-Keap1 [22].…”

Antioxidant Activity Evaluation of Bryophyllum pinnatum (Lam.) Oken Fractions and their Phytocomplexes with β-cyclodextrin

“…Esses processos são intimamente relacionados aos mecanismos fisiopatológicos da formação de ateromas e ateroscleroses. 3 Nesse contexto, a Bryophyllum pinnatum (Lam.) Oken (sinônimo: Kalanchoe pinnata (Lam.…”