The increase in P2C7-induced NOS2 expression suggests that this peptide may be a candidate for DAMP that can participate in the induction of the proinflammatory response of LDL (−) in macrophages, which could contribute to an increase in atherosclerotic plaque instability. Macrophage polarization for M1 was also confirmed by high NO (the final product of NOS2) release induced by P2C7, indicating a shift to the L-arginine/NOS2/NO pathway. These observations also strongly indicate that the P2C7 peptide mimics the macrophage activation effect of LDL (−). The induction of NOS2 by P2C7 peptide is also very relevant in the context of atherosclerosis. The upregulation of NOS2 expression in inflammatory states is related to the presence of pathogen molecules or cytokines that are highly associated with atherosclerosis. The inducible form of NOS releases high levels of NO that exacerbate inflammation, cellular damage, and apoptosis, which enhance atherogenesis [32,33]. NO is a potent mediator of homeostasis of the vascular endothelium. However, when provided by macrophages in the local oxidative stress environments of atherosclerotic lesions, NO is highly consumed by several reactions including that with O−2 (superoxide) to generate ONOO− (peroxynitrite) that can oxidize LDL [34,35]. At high concentrations, peroxynitrite induces cytotoxic effects through peroxynitrous acid formation [36]. NOS2 expression in atherosclerotic lesions (humans/rabbits) has also been observed to co-localize with oxidation-specific epitopes (OSEs) from oxLDL [37]. Our data indicated that the P2C7 peptide induced a M1 macrophage response in addition to inducing the NOS2/NO pathway as well as the upregulation of TNF-α and IL-1α expression. This effect probably occurred via STAT1 activation with the consequent production of NO, and secretion of proinflammatory cytokines such as IL-1α and TNF-α. The IL-1α is constitutively expressed in several cells, even in healthy tissue [38]. However, the inducible expression of IL-1α can be upregulated by NF-κB and AP-1 transcription factors in response to TLR4 activators [39] or oxidative stress [40] and could be related to the overproduction of NO in P2C7-stimulated macrophages.