Deletion of miRNA-22 Induces Cardiac Hypertrophy in Females but Attenuates Obesogenic Diet-Mediated Metabolic Disorders.
Deletion of miRNA-22 Induces Cardiac Hypertrophy in Females but Attenuates Obesogenic Diet-Mediated Metabolic Disorders.
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DOI：
10.33594/000000309
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发表时间：
2020-12-01
期刊：
影响因子：
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通讯作者：
Diniz, Gabriela P
中科院分区：
文献类型：
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作者：
de Oliveira Silva, Tabatha;Lino, Caroline A;Diniz, Gabriela P
背景/目的：肥胖是与心脏代谢并发症相关的一个风险因素。最近，我们报道了在雄性小鼠中，微小RNA - 22（miRNA - 22）缺失可减轻高脂肪饮食诱导的肥胖，并预防血脂异常，且不影响心脏肥大。在本研究中，我们检测了miRNA - 22在致肥胖饮食诱导的雌性小鼠心血管和代谢紊乱中的作用。
方法：野生型（WT）和miRNA - 22基因敲除（miRNA - 22 KO）雌性小鼠分别喂食对照饮食或致肥胖饮食。测量体重增加、肥胖程度、葡萄糖耐量、胰岛素耐量以及血浆总胆固醇和甘油三酯水平。通过组织学分析评估心脏和白色脂肪组织的重塑。使用超声心动图评估心脏功能和形态。采用RNA测序分析来描述雌性小鼠心脏中的信使RNA（mRNA）表达谱。
结果：miRNA - 22缺失减轻了雌性小鼠的体重增加和肥胖程度，并预防了致肥胖饮食诱导的胰岛素抵抗和血脂异常。野生型肥胖雌性小鼠出现心脏肥大。有趣的是，miRNA - 22基因敲除的雌性小鼠出现心脏肥大，但没有左心室功能障碍和心肌纤维化。miRNA - 22缺失和致肥胖饮食均改变了雌性小鼠心脏中的mRNA表达谱。富集分析显示，与心脏收缩力调节、蛋白质折叠和脂肪酸氧化相关的基因在野生型肥胖雌性小鼠的心脏中富集。此外，与甲状腺激素反应、心脏生长和磷脂酰肌醇 - 3激酶（PI3K）信号通路相关的基因在miRNA - 22基因敲除的雌性小鼠心脏中富集。有趣的是，与各自的对照组相比，miRNA - 22基因敲除的肥胖雌性小鼠的Yap1、Egfr和Tgfbr1的mRNA水平降低。
结论：本研究表明，miRNA - 22缺失在雌性小鼠中诱导心脏肥大，但不影响心肌功能。此外，我们的研究结果提示miRNA - 22可作为治疗雌性肥胖相关代谢紊乱的一个潜在治疗靶点。
BACKGROUND/AIMS: Obesity is a risk factor associated with cardiometabolic complications. Recently, we reported that miRNA-22 deletion attenuated high-fat diet-induced adiposity and prevented dyslipidemia without affecting cardiac hypertrophy in male mice. In this study, we examined the impact of miRNA-22 in obesogenic diet-induced cardiovascular and metabolic disorders in females.METHODS: Wild type (WT) and miRNA-22 knockout (miRNA-22 KO) females were fed a control or an obesogenic diet. Body weight gain, adiposity, glucose tolerance, insulin tolerance, and plasma levels of total cholesterol and triglycerides were measured. Cardiac and white adipose tissue remodeling was assessed by histological analyses. Echocardiography was used to evaluate cardiac function and morphology. RNA-sequencing analysis was employed to characterize mRNA expression profiles in female hearts.RESULTS: Loss of miRNA-22 attenuated body weight gain, adiposity, and prevented obesogenic diet-induced insulin resistance and dyslipidemia in females. WT obese females developed cardiac hypertrophy. Interestingly, miRNA-22 KO females displayed cardiac hypertrophy without left ventricular dysfunction and myocardial fibrosis. Both miRNA-22 deletion and obesogenic diet changed mRNA expression profiles in female hearts. Enrichment analysis revealed that genes associated with regulation of the force of heart contraction, protein folding and fatty acid oxidation were enriched in hearts of WT obese females. In addition, genes related to thyroid hormone responses, heart growth and PI3K signaling were enriched in hearts of miRNA-22 KO females. Interestingly, miRNA-22 KO obese females exhibited reduced mRNA levels of Yap1, Egfr and Tgfbr1 compared to their respective controls.CONCLUSION: This study reveals that miRNA-22 deletion induces cardiac hypertrophy in females without affecting myocardial function. In addition, our findings suggest miRNA-22 as a potential therapeutic target to treat obesity-related metabolic disorders in females.