We observed that monocytes and hyperlipidemia modulate VSMCs as follow: (1) Promote their phenotypic switch to macrophages-like cells; (2) reduce the expression of the transcription factor Oct-4 in VSMC, known to be important in preserving VSMC contractile phenotype [16], and upregulate KLF-4 expression shown to promote VSMC phenotypic modulation [17,18]; (3) trigger NLRP3 inflammasome activation and IL-1β secretion by VSMCs as well as; (4) induction of pyroptosis programmed cell death associated with NLRP3 inflammasome activation [21] and with the atherosclerosis plaque rupture [34]. The gene discussed is NLRP3; the disease is atherosclerosis.