**5. Conclusions**

In conclusion, the findings of this study are schematically presented in Figure 8g. TNF-α generally induces ROS production, which influences Akt/AP-1/MMP-9 signaling and cyclin E/cdk2-mediated phosphorylation of Rb, leading to participation in abnormal VSMC migration and proliferation. Conversely, HLP is speculated to play a role in TNF-α antagonist, which contributes to inhibiting ROS generation and VSMC dysfunction. Because our in vitro data demonstrate that HLP inhibited TNFα-induced VSMC migration and proliferation, in vivo results indicate that HLP can effectively improve HFD-promoted atherosclerosis in rabbits via decreasing TNF-α secretion to confirm the anti-atherosclerotic effect of HLP (Figure 8a–d). As shown in Figure 8, HLP can pleiotropically inhibit rabbit atherosclerosis by reducing serum lipid levels, inflammation, atheroscletic lesion, and VSMC migration/proliferation via downregulation of Akt/MMP-9 and upregulation of p53 signals. Taken together, our findings indicate the anti-TNF-α effects of HLP on VSMC could likely contribute to its protection against atherosclerosis and other cardiovascular disorders.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/2076-3921/8/12/620/s1: Table S1. Biological activities of *Hibiscus* leaf in previous studies; Table S2. Polyphenolic compound content (in %) in methanol extracts of *Hibiscus* leaf; Table S3. Sequences of primers used in RT-PCR; Table S4. Antioxidant capacity of HLP in standard antioxidant evaluation; Figure S1. Effect of HLP alone on cell viability in VSMCs; Figure S2. Effect of HLP on TNF-α-induced H2O2 production in VSMC.

**Author Contributions:** Conceptualization, J.-H.C. and H.-H.L.; methodology, C.-C.C. and C.-P.W.; formal analysis, C.-C.C. and C.-P.W.; writing—original draft preparation, C.-C.C.; writing—review and editing, J.-H.C. and H.-H.L.; supervision, J.-H.C. and H.-H.L.; project administration, H.H.L.; funding acquisition, C.-C.C.

**Funding:** This work was supported by a gran<sup>t</sup> from the Antai Medical Care Corporation Antai Tian-Sheng Memorial Hospital (CSMU-TSMH-106-03), Pingtung County, Taiwan.

**Conflicts of Interest:** The authors declare no conflicts of interest.
