Transcriptomic and Lipidomic Analyses Reveal a Novel Antiapoptotic Mechanism of Peptide IRW in the Arteries of Spontaneously Hypertensive Rats through the Reduction of Ceramide Levels and Arachidonic Acid Release

IRW, an antihypertensive peptide derived from ovotransferrin, has been shown to lower blood pressure in spontaneously hypertensive rats (SHRs) by upregulating angiotensin-converting enzyme 2 (ACE2). ACE2 is cardioprotective and a well-documented inhibitor of apoptosis. This study aims to investigate the anti-apoptotic effects of IRW and its underlying mechanism in SHRs' vasculature. IRW was orally administered to SHRs at 15 mg/kg body weight. Transcriptomic analysis of mesenteric arteries revealed enrichment of genes involved in apoptosis suppression by IRW; proteins associated with pro-apoptotic effects, including cytosolic cytochrome c, Bax, caspase-3, and caspase-9, as well as cathepsin B and D, were reduced, whereas the X-linked inhibitor of apoptosis was significantly increased. Lipidomic analysis revealed a notable decrease in mesenteric arterial ceramides (0.040 ± 0.0027% of total lipids) after IRW treatment, likely due to the downregulation of sphingomyelinase and the upregulation of ceramidase, two key enzymes, respectively, responsible for the production and degradation of ceramides. This reduction, along with the IRW-mediated inhibition of arachidonic acid release from membrane phospholipids, contributed to reduced apoptosis. While IRW inhibited the metabolism of released arachidonic acid, some anti-apoptotic oxylipins (prostaglandin E₂ and 5-hydroxyeicosatetraenoic acid) were enhanced. These findings highlight IRW's potential as a modulator of vascular cell survival through multiple antiapoptotic pathways.