Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital, 11009 Cádiz, Spain.
Medicine Department, School of Medicine, University of Cadiz, 11002 Cádiz, Spain.
Int J Mol Sci. 2024 Nov 13;25(22):12161. doi: 10.3390/ijms252212161.
Excess lipid accumulation in the heart is associated with lipotoxicity and cardiac dysfunction due to excessive fatty acid oxidation. Peroxisome proliferator-activated receptor gamma (PPARγ) modulates the expression of key molecules involved in the FA metabolic pathway. Cardiomyocyte-specific overexpression of PPARγ causes dilated cardiomyopathy associated with lipotoxicity in mice. miR-130b-3p has been shown to be downregulated in the plasma of idiopathic dilated cardiomyopathy patients, but its role in modulating cardiomyocyte lipotoxicity via PPARγ remains unclear. Our objective was to investigate the protective role of miR-130b-3p against palmitate-induced lipotoxicity in cardiomyocytes through the modulation of the PPARγ signaling pathway. Human cardiomyoblasts were treated with palmitate. Intracellular lipid accumulation and expression of PPARγ and its downstream targets (, , , ) were analyzed. Mitochondrial oxidative stress was assessed via MitoTracker Green and Redox Sensor Red staining and expression of and . Endoplasmic reticulum stress and apoptosis were determined by examining GRP78, , XBP1s, , and caspase-3 expression. miR-130b-3p overexpression was achieved using transfection methods, and its effect on these parameters was evaluated. Luciferase assays were used to confirm PPARγ as a direct target of miR-130b-3p. Palmitate treatment led to increased lipid accumulation and upregulation of PPARγ and its downstream targets in human cardiomyoblasts. Palmitate also increased mitochondrial oxidative stress, endoplasmic reticulum stress and apoptosis. miR-130b-3p overexpression reduced PPARγ expression and its downstream signaling, alleviated mitochondrial oxidative stress and decreased endoplasmic reticulum stress and apoptosis in palmitate-stimulated cardiomyoblasts. Luciferase assays confirmed PPARγ as a direct target of miR-130b-3p. Our findings suggest that miR-130b-3p plays a protective role against palmitate-induced lipotoxicity in cardiomyocytes by modulating the PPARγ signaling pathway.
心脏中过多的脂质积累与脂毒性和脂肪酸氧化过度导致的心脏功能障碍有关。过氧化物酶体增殖物激活受体γ（PPARγ）调节参与 FA 代谢途径的关键分子的表达。心肌细胞特异性过表达 PPARγ 可导致与脂毒性相关的扩张型心肌病小鼠。已经表明，miR-130b-3p 在特发性扩张型心肌病患者的血浆中下调，但它通过 PPARγ 调节心肌细胞脂毒性的作用尚不清楚。我们的目的是通过调节 PPARγ 信号通路，研究 miR-130b-3p 对脂肪酸诱导的心肌细胞脂毒性的保护作用。用人心肌细胞原代培养物进行棕榈酸盐处理。分析细胞内脂质积累以及 PPARγ 及其下游靶标（、、、）的表达。通过 MitoTracker Green 和 Redox Sensor Red 染色以及和的表达来评估线粒体氧化应激。通过检测 GRP78、、XBP1s、、和 caspase-3 的表达来确定内质网应激和细胞凋亡。通过转染方法实现 miR-130b-3p 的过表达，并评估其对这些参数的影响。荧光素酶测定用于确认 PPARγ 是 miR-130b-3p 的直接靶标。棕榈酸盐处理导致人心肌细胞中原代培养物中脂质积累增加和 PPARγ 及其下游靶标的上调。棕榈酸盐还增加了线粒体氧化应激、内质网应激和细胞凋亡。miR-130b-3p 的过表达降低了 PPARγ 的表达及其下游信号，减轻了棕榈酸盐刺激的心肌细胞中的线粒体氧化应激并减少了内质网应激和细胞凋亡。荧光素酶测定证实 PPARγ 是 miR-130b-3p 的直接靶标。我们的研究结果表明，miR-130b-3p 通过调节 PPARγ 信号通路在心肌细胞中发挥对棕榈酸诱导的脂毒性的保护作用。
