Division of Cardiology, Department of Medicine, University of California, Los Angeles, CA, USA.
Metabolism Theme, David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095, USA.
Nat Commun. 2022 Jul 4;13(1):3850. doi: 10.1038/s41467-022-31544-5.
Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypothesis in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we find that mitochondrial gene expression is highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a "two-hit" mouse model of HFpEF confirm that mitochondrial function differs between sexes and is strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identify the mitochondrial gene Acsl6 as a genetic determinant of diastolic function. We validate its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.
射血分数保留型心力衰竭（HFpEF）存在性别偏向，女性比男性更为常见，我们假设线粒体性别差异可能是这种偏向的基础。作为对小鼠心力衰竭遗传研究的一部分，我们观察到与男性相比，女性心脏线粒体 DNA 水平和功能往往降低。我们还观察到在人类队列中，编码线粒体蛋白的基因表达在男性中高于女性。我们在称为杂交小鼠多样性面板（HMDP）的一组遗传多样化近交系小鼠中检验了我们的假设。实际上，我们发现线粒体基因表达与舒张功能高度相关，舒张功能是 HFpEF 的一个关键特征。与此一致的是，HFpEF 的“双打击”小鼠模型研究证实，线粒体功能在性别之间存在差异，并与许多 HFpEF 特征密切相关。通过整合来自人类心力衰竭和小鼠 HMDP 队列的数据，我们确定线粒体基因 Acsl6 是舒张功能的遗传决定因素。我们使用心脏中的腺病毒过表达来验证其在 HFpEF 中的作用。我们的结论是，线粒体功能的性别差异部分导致了舒张功能的性别偏向。
