Shexiang Baoxin Pill (SBP), derived from the traditional Chinese medicine, has been broadly applied for the treatment of cardiovascular diseases including coronary heart disease, heart failure, and hypertension in East Asia for decades. Emerging pharmacological studies have revealed that SBP displays pleiotropic roles in protecting the cardiovascular system, as seen by the promotion of angiogenesis, amelioration of inflammation, improvement of endothelium dysfunction, mitigation of dyslipidemia, repression of vascular smooth muscle cell proliferation, and migration and restraint of cardiac remodeling. In terms of clinical practice, the clinical trials and meta-analyses have proved the efficacy and safety of SBP. In this review, we, for the first time, systematically summarize the cardioprotective effects and underlying mechanisms of SBP and provide novel insights into future research directions of SBP based on the experimental and clinical perspectives.

Background: Atherosclerosis is a chronic vascular disease posing a great threat to public health. We investigated whether rosuvastatin (RVS) enhanced autophagic activities to inhibit lipid accumulation and polarization conversion of macrophages and then attenuate atherosclerotic lesions. Methods: All male Apolipoprotein E-deficient (ApoE^−/−) mice were fed high-fat diet supplemented with RVS (10 mg/kg/day) or the same volume of normal saline gavage for 20 weeks. The burden of plaques in mice were determined by histopathological staining. Biochemical kits were used to examine the levels of lipid profiles and inflammatory cytokines. The potential mechanisms by which RVS mediated atherosclerosis were explored by western blot, real-time PCR assay, and immunofluorescence staining in mice and RAW264.7 macrophages. Results: Our data showed that RVS treatment reduced plaque areas in the aorta inner surface and the aortic sinus of ApoE^−/− mice with high-fat diet. RVS markedly improved lipid profiles and reduced contents of inflammatory cytokines in the circulation. Then, results of Western blot showed that RVS increased the ratio LC3II/I and level of Beclin 1 and decreased the expression of p62 in aortic tissues, which might be attributed to suppression of PI3K/Akt/mTOR pathway, hinting that autophagy cascades were activated by RVS. Moreover, RVS raised the contents of ABCA1, ABCG1, Arg-1, CD206 and reduced iNOS expression of arterial wall, indicating that RVS promoted cholesterol efflux and M2 macrophage polarization. Similarly, we observed that RVS decreased lipids contents and inflammatory factors expressions in RAW264.7 cells stimulated by ox-LDL, accompanied by levels elevation of ABCA1, ABCG1, Arg-1, CD206 and content reduction of iNOS. These anti-atherosclerotic effects of RVS were abolished by 3-methyladenine intervention. Moreover, RVS could reverse the impaired autophagy flux in macrophages insulted by chloroquine. We further found that PI3K inhibitor LY294002 enhanced and agonist 740 Y-P weakened the autophagy-promoting roles of RVS, respectively. Conclusions: Our study indicated that RVS exhibits atheroprotective effects involving regulation lipid accumulation and polarization conversion by improving autophagy initiation and development via suppressing PI3K/Akt/mTOR axis and enhancing autophagic flux in macrophages.

Inflammatory responses in macrophages, endothelial cells, and vascular smooth muscle cells play crucial roles in the development of atherosclerosis. Baicalein, a flavonoid phytochemical, possesses anti‐inflammatory properties, but the underlying mechanisms of its action are not fully understood. The aim of this study was to explore whether baicalein inhibited inflammatory activities in RAW264.7, HUVEC, and MOVAS cells and to analyze its underlying mechanisms. Our results showed that baicalein treatment effectively reduced the levels of IL‐6, TNF‐α, PAI‐1, and MMP‐9 released by these cells upon stimulation with Ang II or ox‐LDL. We discovered that the molecular mechanisms underlying baicalein suppression of the generation of proinflammatory cytokines were associated with the inhibition of MAPK/NF‐κB pathway activity. Moreover, Ang II and ox‐LDL intervention decreased the content of Mfn‐2 in the three types of cells, but incubation of baicalein alleviated the Ang II/ox‐LDL‐induced reduction of Mfn‐2 levels. Adv‐Mfn2 treatment not only increased the expression of Mfn‐2 but also reduced the levels of phosphorylated ERK1/2, p38, JNK, and NF‐κB, followed by a decrease in the concentrations of IL‐6, TNF‐α, PAI‐1, and MMP‐9 in the supernatant. Furthermore, our findings indicated that baicalein treatment markedly suppressed the decrease in AMPK activity induced with Ang II and ox‐LDL, and incubation with Compound C reversed the effects of baicalein on AMPK activation and Mfn‐2 expression. In conclusion, our data suggest that baicalein shows anti‐inflammatory properties, probably by activating the AMPK/Mfn‐2 axis, accompanied by inhibition of downstream MAPKs/NF‐κB signaling transduction.

Anthracyclines, such as doxorubicin (DOX), are among the effective chemotherapeutic drugs for various malignancies. However, their clinical use is limited by irreversible cardiotoxicity. This study sought to determine the role of neuraminidase 1 (NEU1) in DOX-induced cardiomyopathy and the potential cardio-protective effects of NEU1 inhibitor oseltamivir (OSE). Male Sprague–Dawley (SD) rats were randomized into three groups: control, DOX, and DOX + OSE. NEU1 was highly expressed in DOX-treated rat heart tissues compared with the control group, which was suppressed by OSE administration. Rats in the DOX + OSE group showed preserved cardiac function and were protected from DOX-induced cardiomyopathy. The beneficial effects of OSE were associated with the suppression of dynamin-related protein 1 (Drp1)-dependent mitochondrial fission and mitophagy. In detail, the elevated NEU1 in cardiomyocytes triggered by DOX increased the expression of Drp1, which subsequently enhanced mitochondrial fission and PINK1/Parkin pathway-mediated mitophagy, leading to a maladaptive feedback circle towards myocardial apoptosis and cell death. OSE administration selectively inhibited the increased NEU1 in myocardial cells insulted by DOX, followed by reduction of Drp1 expression, inhibition of PINK1 stabilization on mitochondria, and Parkin translocation to mitochondria, thus alleviating excessive mitochondrial fission and mitophagy, alleviating subsequent development of cellular apoptotic process. This work identified NEU1 as a crucial inducer of DOX-induced cardiomyopathy by promoting Drp1-dependent mitochondrial fission and mitophagy, and NEU1 inhibitor showed new indications of cardio-protection against DOX cardiotoxicity.

Sepsis is a dysregulated systemic inflammatory response that often leads to cardiac dysfunction, which is termed sepsis-induced cardiomyopathy (SIC). Harmine, a natural β-carboline alkaloid compound, has been shown to exert pharmacological effects on several diseases. Here, we investigated whether harmine protected against SIC development and the underlying mechanisms. In vitro, the expression of the M1 phenotype markers iNOS and COX-2 was increased in RAW 264.7 cells stimulated with lipopolysaccharide (LPS), but this effect was reversed by the harmine intervention. Furthermore, LPS-induced increases in the levels of inflammatory cytokines, including IL-1β, IL-6, TNF-α, iNOS, COX-2, PGE2 and TXB2, generated by macrophages were suppressed when the cells were pretreated with harmine. Meanwhile, our findings showed that harmine administration effectively attenuated inflammation and apoptosis in H9c2 cells in the proinflammatory environment produced by macrophages, as evidenced by reductions in NLRP3 and cleaved caspase 3 levels and the p-NF-κB/NF-κB ratio. The western blot results indicated that the mechanisms underlying harmine-mediated inhibition of M1 polarization might be associated with suppression of STAT1/3, NF-κB and MAPK activation. Furthermore, an LPS injection induced cardiac dysfunction and decreased the survival rate of mice, which were alleviated by harmine treatment, and the relevant mechanism was possibly attributed to a drug-induced attenuation of the inflammatory and apoptotic processes in cardiomyocytes. Collectively, these results implied that harmine treatment protected against SIC by suppressing M1 phenotypic polarization and inflammation in macrophages.