Background and aims: Beyond the regulation of cholesterol metabolism, a number of pleiotropic extrahepatic functions of Proprotein convertase subtilisin/kexin type 9 (PCSK9) have been increasingly identified. An increase of PCSK9 action in vascular smooth muscle cells (VSMC) could play a role in the vascular damage in metabolic disorders, such as obesity and diabetes. The main purpose of this study was to verify whether PCSK9 expression in VSMC was: (i) affected by insulin-resistance state, (ii) influenced by high glucose exposure, (iii) modulated by PCSK-9 inhibition. Methods: In cultured rat aortic VSMC from lean insulin-sensitive Zucker rat (LZR) and obese insulin-resistant Zucker rat (OZR) exposed for 24 hours to 25mmol/L D-Glucose (HG) with or without the monoclonal antibodies against PCSK9 Alirocumab or Evolocumab (40microgr/mL) or the synthetic PCSK9-binding peptide PEP2-8 (10micromol/L), we evaluated PCSK9 expression and related pathways involved. Results: In VSMCs from LZR: HG increased PCSK9 expression (n=10, p<0.0001) by oxidative stress-mediated mechanisms involving the activation of PKC/NADPH-oxidase/MAPK/ERK-1/2 axis pathway and with effects reduced by Alirocumab (n=6, p=0.001), Evolocumab (n=6, p=0.005), or PEP2-8 (n=6, p=0.01). In VSMC from OZR: in comparison with LZR, we found basal PCSK9 overexpression (n=12, p<0.0001), not furtherly influenced by HG but significantly reduced by PKC/NADPH-oxidase pathways inhibitors (n=6, p=0.01-0.0001), and the PCSK9 inhibitors Alirocumab, Evolocumab and PEP2-8 (n=6, p=0.03-0.0001). Conclusions: Collectively, these findings indicate that in insulin-sensitive state the exposure to HG may impair VSMC function also through oxidative stress-mediated mechanisms leading to increase of PCSK9 expression. This phenomenon can be attenuated by both outside (Alirocumab, Evolocumab) and inside (PEP2-8) acting PCSK9 inhibitors, thus indicating that PCSK9 can sustain its expression and secretion in an autocrine manner. In insulin-resistant state, VSMCs show an oxidative stress-dependent basal overexpression of PCSK9, not furtherly influenced by HG but, at least partially, corrected by PCSK9 inhibitors.