HIF-1α Cardioprotection in COVID-19 Patients.
HIF-1α Cardioprotection in COVID-19 Patients.
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DOI：
10.1016/j.jacbts.2021.12.001
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Chaudhry HW
中科院分区：
文献类型：
--
作者：
Wang BJ;Vadakke-Madathil S;Croft LB;Brody RI;Chaudhry HW
超过一半(58%)的患者有持续心脏受累的心肌损伤，并可在感染SARS-CoV-2几个月后发现。1 SARS-CoV-2感染直接引发呼吸系统疾病，并经常导致肺和心血管组织缺氧。2低氧诱导因子-1a是组织缺氧的主要转录调节因子，已有报道可降低血管紧张素转换酶2的表达，从而可能抑制SARS-CoV-2的细胞侵袭，减轻新冠肺炎的严重程度。值得注意的是，据报道，SARS-CoV-2在高海拔地区的致病性降低，可能是由于适应低氧的当地居民肺部ACE2减少所致。3在本研究中，我们检测了8例已知SARS-CoV-2感染的患者(年龄39~76岁，中位年龄)的尸检标本中的组织缺氧标志物。根据左心室射血分数将新冠肺炎患者分为2组。LVEF和GT；50%的患者被归类为“LVEF正常”(58%到63%)，而LVEF和Lt；45%的患者被归类为“低LVEF”(33%到43%)。三个非心源性死因供者的非COVID心脏作为对照心脏(年龄范围59-79岁，中位年龄60岁)。免疫组织化学检测显示，LVEF值正常的患者心脏中HIF-1a的表达显著高于LVEF值低的患者，而非COVID患者的心脏中HIF-1a+细胞较少(图1A)。低LVEF值组和正常LVEF值组HIF1a免疫阳性细胞均定位于CD31+内皮细胞。值得注意的是，心脏中的所有HIF-1a+细胞都是末端脱氧核苷酸转移酶dUTP缺口末端标记(TUNEL)阴性(图1A)。这些发现提示，但并不能证明，低氧诱导因子-1a上调可增强新冠肺炎患者心脏内皮细胞的细胞保护反应。在LVEF正常的患者中，HIF-1a主要在非心肌细胞中表达，有核或核周定位(图1B)。相比之下，在低LVEF患者中，HIF-1a在心肌细胞核内以斑点状聚集(图1B)。然后我们用透射电子显微镜检查了细胞核和肌节的超微结构。与非COVID对照心脏相似，正常左心室射血分数(LVEF)心脏的核膜厚而致密(图1B)。在低LVEF心脏，核膜较薄，不破坏板层膜。低左心室射血分数低的心脏可见肌节损伤，表现为Z线肿胀、I带模糊、肌节收缩、肌原纤维排列扭曲，而正常左心室射血分数组和非COVID对照组的心肌肌节排列不明显。与对照组相比，新冠肺炎左心室射血分数降低组和正常组心肌线粒体明显减少。线粒体分散在肌原纤维中，而不是像对照组心脏那样规则地排列成行。此外，低左心室射血分数低的心脏线粒体较小，冠状突起肿胀。我们还用核膜标记物lamin B1和HIF-1a对心脏切片进行了联合免疫染色。在非冠状病毒感染的心脏中，层蛋白B1在所有细胞中持续表达(图1B)。在缺乏HIF-1a表达的新冠肺炎心肌细胞中，层蛋白B1在正常左心室射血分数心脏中表达降低，而在低左心室射血分数心脏中检测不到。HIF-1a-肌细胞胞核增大或形状不规则。这一观察结果与最近关于SARS-CoV-2感染诱导的…中核DNA丢失的报道一致
Myocardial injury with sustained cardiac involvement is noted in more than half (58%) of patients and can be detected months after SARS-CoV-2 infection. 1 SARS-CoV-2 infection directly triggers respiratory illness and frequently leads to both pulmonary and cardiovascular tissue hypoxia. 2 Hypoxia-inducible factor (HIF)-1a is a master transcriptional regulator of tissue hypoxia and has been reported to decrease the expression of angiotensin-converting enzyme 2 (ACE2), which may potentially attenuate SARS-CoV-2 cell entry and lessen the severity of COVID-19. Of note, decreased pathogenicity of SARS-CoV-2 has been reported at high-altitude regions, possibly secondary to reduced ACE2 in lungs of local inhabitants who are acclimatized to hypoxia. 3 In this study, we examined markers of tissue hypoxia in post-mortem samples of 8 patients (age range 39 to 76 years; median age 64 years) with known SARS-CoV-2 infection. The COVID-19 patients were divided into 2 groups based on left ventricular ejection fraction (LVEF). Patients with LVEF> 50% were categorized as “normal LVEF”(range 58% to 63%), and patients with LVEF< 45% as “low LVEF”(range 33% to 43%). Three non-COVID hearts from donors of noncardiac cause of death served as control hearts (age range 59 to 79 years, median age 60 years). HIF-1a expression, which was determined by immunohistochemistry, was significantly higher in the hearts of patients with normal LVEF in comparison to the low LVEF group, whereas scant HIF-1a+ cells were observed in non-COVID hearts (Figure 1A). HIF1a was immunolocalized to CD31+ endothelial cells in both the low and normal LVEF groups. Notably, all HIF-1a+ cells in the heart were terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-negative (Figure 1A). These findings suggest, but do not prove, that HIF-1a up-regulation confers cytoprotective responses in endothelial cells in the hearts of COVID-19 patients. In normal LVEF patients, HIF-1a was predominantly expressed in nonmyocytes, with either nuclear or perinuclear localization (Figure 1B). By contrast, in low LVEF patients, HIF-1a accumulated in a speckled pattern in cardiomyocyte nuclei (Figure 1B). We then examined nuclear and sarcomeric ultrastructure by transmission electron microscopy. Similar to non-COVID control hearts, the nuclear envelope appeared thick and dense in the normal LVEF hearts (Figure 1B). In low LVEF hearts, the nuclear envelope was thinner, without disruption of the lamin membrane. Sarcomeric damage was noted in the low LVEF heart as evidenced by swollen Z lines, smeared I bands, contracted sarcomeres, and distorted myofibril arrangements, whereas sarcomere disarray was not apparent in the normal LVEF group or in the non-COVID control hearts. Fewer mitochondria were detected in the hearts of low and normal LVEF groups of COVID-19 as compared with the hearts of control subjects. The mitochondria were scattered among myofibrils, rather than regularly aligned rows, as noted in control hearts. Additionally, mitochondria in low LVEF hearts were smaller, with swollen cristae. We also examined heart sections by coimmunostaining with nuclear envelope marker lamin B1 and HIF-1a. In non-COVID hearts, lamin B1 was continuously expressed in all cells (Figure 1B). In COVID-19 cardiomyocytes that lacked HIF-1a expression, lamin B1 expression was decreased in normal LVEF hearts, whereas it was undetectable in low LVEF hearts. Nuclei of the HIF-1a- myocytes appeared to be enlarged or irregularly shaped. This observation is in line with a recent report of loss of nuclear DNA in SARS-CoV-2–infected induced …
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影响因子：
17.1
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