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Mechanisms Responsible for Ceramide‐Induced Vascular Dysfunction Observed in vitro are Operational in vivo
Author(s) -
Bharath Leena,
Ruan Ting,
Li Youyou,
Zhang Quanjiang,
Abel E Dale,
Symons J David
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.818.11
Subject(s) - ceramide , enos , protein phosphatase 2 , sphingolipid , protein kinase b , endocrinology , medicine , endothelial dysfunction , microbiology and biotechnology , acid sphingomyelinase , biology , phosphatase , chemistry , biochemistry , signal transduction , phosphorylation , nitric oxide , nitric oxide synthase , apoptosis
When arterial accumulation of the free fatty acid (FFA) metabolite ceramide is prevented, endothelial dysfunction and hypertension that develop in obese mice is less severe. To elucidate molecular mechanisms responsible for the deleterious effects of this sphingolipid we challenged endothelial cells (ECs) with a potent stimulus for ceramide accrual i.e., the FFA palmitate. Ceramide that accumulates in response to palmitate colocalizes with inhibitor 2 of protein phosphatase 2A (I2PP2A) within the cell. When this interaction occurs the restraint that I2PP2A normally confers upon protein phosphatase 2A (PP2A) is relieved, and PP2A translocates to the cell membrane where it colocalizes with eNOS. When PP2A binds with eNOS the requisite interactions among Akt‐Hsp90‐eNOS are disrupted and eNOS enzyme function is compromised. All palmitate‐induced effects in ECs can be prevented using a variety of approaches that limit ceramide biosynthesis or inhibit PP2A activity. Our most recent findings indicate these mechanisms observed in vitro are operational in vivo . When ceramide accumulation or PP2A activation are prevented in vessels from obese mice through genetic or pharmacological procedures, respectively, disruptions among Akt‐Hsp90‐eNOS, endothelial dysfunction, and/or hypertension that otherwise occur in mice with diet‐induced obesity are not observed. Taken together, mechanistic insight concerning the contribution from ceramide to EC dysfunction obtained from experiments performed in vitro can be translated to a pre‐clinical murine model of obesity.