Department of Medicinal Chemistry and Natural Medicine Chemistry, Department of Pharmacognosy, College of Pharmacy, Harbin Medical University, Harbin 150081, China.
Department of Medicinal Chemistry and Natural Medicine Chemistry, Department of Pharmacognosy, College of Pharmacy, Harbin Medical University, Harbin 150081, China; State-Province Key Laboratory of Biomedicine-Pharmaceutics of China, Harbin Medical University, Harbin 150081, China.
Phytomedicine. 2022 Feb;96:153840. doi: 10.1016/j.phymed.2021.153840. Epub 2021 Nov 6.
Pulmonary vascular remodeling is the key pathological feature of pulmonary arterial hypertension (PAH) characterized by a pattern of lipid-related insulin resistance(IR), hormonal derangements and metabolic reprogramming. Our previous studies have demonstrated osthole as natural coumarin compound derived from traditional Chinese medicine is a promising agent for the treatment of pulmonary vascular remodeling in PAH.
The present study sought to delineate lipid metabolic modulatory mechanism of osthole against pulmonary vascular remodeling by employing an interdisciplinary strategy.
Rat model with PAH induced with MCT and PASMCs proliferation model induced with PDGF-BB were established in this study. Serum and lung tissues were used to lipid-related IR, hormone related indexes, pulmonary vascular remodeling analysis. Then, lipid metabolic gene, key enzymes, metabolites and cell proliferation indexes were examined to investigate metabolic regulatory mechanism in vivo and vitro model of PAH.
Osthole significantly showed improvement of lipid-related IR and hormone dysregulation in rats with PAH evidenced by elevating testosterone, androgen receptor and cyclic guanosine monophosphate (cGMP), inhibiting phosphodiesterase-5(PDE-5), modulating lipid-related IR indexes total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglyceride (TG)/HDL-C ratio. Additionally, osthole limited key metabolic gene and enzymes to inhibit accumulation of decadienyl-l-carnitine in lipid metabolism, thus to promote oxidative phosphorylation and ATP production through inhibition of miRNA-22-3p, fatty acid translocase (CD36), fatty acid synthase (FAS), phospholipase A2 (PLA2), carnitine palmitoyltransferase 1A (CPT1A), hexokinase 2 (HK2), activation of metabolic switch isocitrate dehydrogenase 3α (IDH3α), NADH dehydrogenase 1 (ND1). We found for the first time miRNA-22-3p modulated PASMCs proliferation and vascular remodeling by regulating lipid metabolism reprogramming. Those modifications uncovered therapeutic mechanism of osthole against pulmonary vascular remodeling.
Our findings revealed the function of miRNA-22-3p in PASMCs and demonstrated a novel mechanism that miRNA-22-3p as a regulator can be targeted by osthole to greatly restore dysregulated lipid metabolism thus to alleviate pulmonary vascular remodeling in PAH, which provides novel insight into the potential therapeutic target for PAH, further highlights the development potential of osthole derived new drug against PAH.
肺血管重构是肺动脉高压（PAH）的关键病理特征，其特征是存在脂质相关胰岛素抵抗（IR）、激素失调和代谢重编程。我们之前的研究表明，蛇床子素是一种源自中药的天然香豆素化合物，是治疗 PAH 肺血管重构的有前途的药物。
本研究采用跨学科策略，阐述蛇床子素对肺血管重构的脂质代谢调节机制。
本研究建立了 MCT 诱导的大鼠 PAH 模型和 PDGF-BB 诱导的 PASMCs 增殖模型。利用血清和肺组织检测脂质相关 IR、激素相关指标、肺血管重构分析。然后，在体内和体外 PAH 模型中检测脂质代谢基因、关键酶、代谢物和细胞增殖指标，以研究代谢调节机制。
蛇床子素显著改善了 PAH 大鼠的脂质相关 IR 和激素失调，表现为睾酮、雄激素受体和环鸟苷单磷酸（cGMP）升高，磷酸二酯酶-5（PDE-5）抑制，调节脂质相关 IR 指标总胆固醇（TC）、高密度脂蛋白胆固醇（HDL-C）、甘油三酯（TG）/HDL-C 比值。此外，蛇床子素限制关键代谢基因和酶，抑制脂质代谢中 decadienyl-l-carnitine 的积累，从而通过抑制 miRNA-22-3p、脂肪酸转运蛋白（CD36）、脂肪酸合酶（FAS）、磷脂酶 A2（PLA2）、肉碱棕榈酰转移酶 1A（CPT1A）、己糖激酶 2（HK2）、代谢开关异柠檬酸脱氢酶 3α（IDH3α）、NADH 脱氢酶 1（ND1）的激活，促进氧化磷酸化和 ATP 生成。我们首次发现 miRNA-22-3p 通过调节脂质代谢重编程来调节 PASMCs 的增殖和血管重构。这些修饰揭示了蛇床子素治疗肺血管重构的机制。
我们的发现揭示了 miRNA-22-3p 在 PASMCs 中的功能，并证实了 miRNA-22-3p 作为调节剂的新机制可以被蛇床子素靶向，从而极大地恢复失调的脂质代谢，从而缓解 PAH 中的肺血管重构，为 PAH 的潜在治疗靶点提供了新的见解，进一步凸显了蛇床子素衍生新药治疗 PAH 的开发潜力。
