Diabetic cardiomyopathy (DbCM) is characterized by diastolic dysfunction, which progresses into heart failure and aberrant electrophysiology in diabetic patients. Dyslipidemia in type 2 diabetic patients leads to the accumulation of lipid droplets (LDs) in cardiomyocytes and results in lipid toxicity which has been suggested to drive DbCM. It is aimed to explore potential pathways that may boost LDs degradation in DbCM and restore cardiac function. LDs accumulation resulted in an increase in lipid toxicity in DbCM hearts is confirmed. Microlipophagy pathway, rather than traditional macrolipophagy, is activated in DbCM hearts. RNA-Seq data and Rab7-CKO mice implicate that Rab7 is a major modulator of the microlipophagy pathway. Mechanistically, Rab7 is phosphorylated at Tyrosine 183, which allows the recruitment of Rab-interacting lysosome protein (Rilp) to proceed LDs degradation by lysosome. Treating DbCM mice with Rab7 activator ML-098 enhanced Rilp level and rescued the observed cardiac dysfunction. Overall, Rab7-Rilp-mediated microlipophagy may be a promising target in the treatment of lipid toxicity in DbCM is suggested.
Min Fu,Yuan Li,Jingjing Liu,Junjie Liu,Jiaoxia Wei,Yuxin Qiao,Hanxin Zhong,Dongyang Han,Haitao Lu,Li Yao
Background Pulmonary hypertension (PH) is a severe cardio-pulmonary vascular disease, involves complex molecular mechanism especially during the pathological process of pulmonary vascular remodeling, brings a significant challenge to clinical treatment and thus resulting in high mortality rates. Classic Traditional Chinese medicine formula, Zhishi Xiebai Guizhi Decoction (ZXGD), holds therapeutic potential for PH. In present study, we sought to explore therapeutic potential of ZXGD against PH in rats. Methods We employed a combination methods of chemical profiling, echocardiographic, morphologic measurements, molecular biology, rats models and cultured pulmonary artery smooth muscle cells (PASMCs) to achieve this. Results Eighteen compounds were precisely identified in ZXGD using UHPLC-QTOF-MS/MS. Our data demonstrated ZXGD could alleviate PH by reducing pulmonary artery pressure and alleviating pulmonary vascular remodeling in rats. Specifically, ZXGD was found to intervene in abnormal expansion of PASMCs, thereby attenuating pulmonary vascular remodeling. ZXGD was also observed to modulate expressions of HIF-1α, ROS, and Nrf2 to alleviate hypoxia and oxidative stress. Additionally, ZXGD significantly regulated disorders in pro-inflammatory cytokines, thus mitigating inflammation. Furthermore, ZXGD decreased levels of decadienyl- l -carnitine and LDL-C, while elevating HDL-C and lipid droplet counts, thereby reducing cholesterol and lipid toxicity and preserving mitochondrial function. Importantly, inhibition of HIF-1α reversed expression of key pathological triggers for pulmonary vascular remodeling. Neohesperidin and naringin in ZXGD extract were identified as the primary contributors to its pharmacological effects against PH. Conclusion Altogether, our study empirically explored therapeutic potential and pharmacological mechanisms of ZXGD in treating PH, offering a groundwork for the development of novel anti-PH drugs. Graphical Supplementary Information The online version contains supplementary material available at 10.1186/s13020-024-01039-0.
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