Sexually dimorphic effects of SARM1 deletion on cardiac NAD+ metabolism and function.
Sexually dimorphic effects of SARM1 deletion on cardiac NAD+ metabolism and function.
复制标题
SARM1 缺失对心脏 NAD 代谢和功能的性别二态性影响。
DOI：
10.1152/ajpheart.00370.2022
复制
发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Lee,ChiFung
中科院分区：
文献类型：
--
作者：
Nizami,HinaLateef;Minor,KeatonE;Chiao,YingAnn;Light,ChristineM;Lee,ChiFung
在心脏病及其危险因素中反复观察到烟酰胺腺嘌呤二核苷酸（NAD+）下降。虽然促进NAD+合成以提高NAD+水平的策略改善心脏功能，但对抑制NAD+消耗是否具有治疗作用的研究较少。在这项研究中，我们研究了不育-α和TIR模体含有1（SARM 1）NAD+水解酶在小鼠心脏中的作用，使用全球SARM 1敲除小鼠（KO）。通过超声心动图评估雄性和雌性KO小鼠和野生型（WT）对照的心脏功能。收集心脏进行生化、组织学和分子分析。我们发现，心脏NAD+池在雌性KO小鼠中升高，但仅在雄性KO小鼠中有增加的趋势。SARM 1缺失诱导雄性小鼠NAD+代谢转录物的变化数量多于雌性小鼠。与WT对应小鼠相比，雄性和雌性KO小鼠的体重、心脏收缩和舒张功能以及几何形状均未发生变化。与WT小鼠相比，雄性KO小鼠的心脏胶原蛋白水平显示出较小但显著的升高，但在雌性小鼠中未检测到胶原蛋白水平的差异。增加的胶原蛋白水平与雄性KO小鼠中更多的改变的促纤维化和衰老相关的炎症基因相关，但在雌性KO小鼠中则不然。新&值得注意的是，我们首次在小鼠心脏中检测了SARM 1缺失对NAD+池、NAD+代谢的转录物和纤维化途径的影响。我们观察了SARM 1缺失的性二型效应。这些性别依赖性效应如何影响雄性和雌性小鼠对心脏应激反应中SARM 1缺陷的结果，值得进一步研究。SARM 1缺失导致的心脏NAD+池升高提供了靶向SARM 1可能逆转疾病相关NAD+下降的证据。
Nicotinamide adenine dinucleotide (NAD+) decline is repeatedly observed in heart disease and its risk factors. Although strategies promoting NAD+synthesis to elevate NAD+levels improve cardiac function, whether inhibition of NAD+consumption can be therapeutic is less investigated. In this study, we examined the role of sterile-α and TIR motif containing 1 (SARM1) NAD+hydrolase in mouse hearts, using global SARM1-knockout mice (KO). Cardiac function was assessed by echocardiography in male and female KO mice and wild-type (WT) controls. Hearts were collected for biochemical, histological, and molecular analyses. We found that the cardiac NAD+pool was elevated in female KO mice, but only trended to increase in male KO mice. SARM1 deletion induced changes to a greater number of NAD+metabolism transcripts in male mice than in female mice. Body weights, cardiac systolic and diastolic function, and geometry showed no changes in both male and female KO mice compared with WT counterparts. Male KO mice showed a small, but significant, elevation in cardiac collagen levels compared with WT counterparts, but no difference in collagen levels was detected in female mice. The increased collagen levels were associated with greater number of altered profibrotic and senescence-associated inflammatory genes in male KO mice, but not in female KO mice.NEW & NOTEWORTHYWe examined the effects of SARM1 deletion on NAD+pool, transcripts of NAD+metabolism, and fibrotic pathway for the first time in mouse hearts. We observed the sexually dimorphic effects of SARM1 deletion. How these sex-dependent effects influence the outcomes of SARM1 deficiency in male and female mice in responses to cardiac stresses warrant further investigation. The elevation of cardiac NAD+pool by SARM1 deletion provides evidence that targeting SARM1 may reverse disease-related NAD+decline.