Bertazzo Julia, Oyama Yoshimasa, Gordon Finneas, Walker Lori, de la Garza Eckle Tobias
Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Ann Transl Med. 2025 Aug 31;13(4):40. doi: 10.21037/atm-25-27. Epub 2025 Aug 26.
Studies on light-elicited endothelial period circadian regulator 2 (PER2) mediated cardioprotection revealed a critical role of PER2/hypoxia inducible factor 1 alpha (HIF1A) regulated endothelial factor ANGPTL4 for endothelial barrier protection during myocardial ischemia and reperfusion injury (IRI). Based on these observations, we deepened our studies on light-elicited cardioprotective mechanisms.
All animal and human studies had Institutional Animal Care and Use Committee (IACUC) and Colorado Multiple Institutional Review Board (COMIRB) approval. To study myocardial IRI, an in-situ mouse model for myocardial IRI was used. To study light-elicited mechanisms during myocardial IRI, endothelial-specific -deficient mice were treated with the PER2 enhancer nobiletin (NOB), with the HIF1A activator dimethyloxalylglycine (DMOG), or with recombinant ANGPTL4. To evaluate whether light could increase ANGPTL4 or decrease troponin levels in patients, we exposed patients undergoing elective spine surgery postoperatively for 5 days with intense light for 30 minutes at sunrise. Patient's plasma samples were tested for melatonin, ANGPTL4 and troponin levels using enzyme-linked immunosorbent assay (ELISA).
The PER2 enhancer NOB or the HIF1A activator DMOG protected from myocardial IRI, which was abolished in endothelial-specific -deficient mice. ANGPTL4 was able to overcome an endothelial deficiency and revealed protection during myocardial IRI in endothelial-specific -deficient or control mice. Intense light therapy in patients undergoing non-cardiac surgery showed increased ANGPTL4 and decreased troponin plasma levels.
Our study demonstrates that only the PER2/HIF1A downstream target ANGPTL4 can overcome an endothelial deficiency. Moreover, we discovered that intense light therapy in patients following non-cardiac surgery can be used to increase plasma levels of the endothelial protective factor ANGTL4 and decrease troponin levels, an indicator of myocardial injury in non-cardiac surgery (MINS). Further research with larger, more diverse human cohorts and long-term follow-up is needed to validate these findings and develop targeted therapies.
关于光诱导内皮生物钟调节因子2（PER2）介导的心脏保护作用的研究表明，在心肌缺血再灌注损伤（IRI）期间，PER2/缺氧诱导因子1α（HIF1A）调节的内皮因子血管生成素样蛋白4（ANGPTL4）对内皮屏障保护起着关键作用。基于这些观察结果，我们深入研究了光诱导的心脏保护机制。
所有动物和人体研究均获得机构动物护理和使用委员会（IACUC）以及科罗拉多多机构审查委员会（COMIRB）的批准。为了研究心肌IRI，使用了原位小鼠心肌IRI模型。为了研究心肌IRI期间的光诱导机制，对内皮特异性缺失的小鼠给予PER2增强剂诺必亭（NOB）、HIF1A激活剂二甲基草酰甘氨酸（DMOG）或重组ANGPTL4进行治疗。为了评估光是否能增加患者体内ANGPTL4水平或降低肌钙蛋白水平，我们让接受择期脊柱手术的患者在术后5天日出时接受30分钟强光照射。使用酶联免疫吸附测定（ELISA）检测患者血浆样本中的褪黑素、ANGPTL4和肌钙蛋白水平。
PER2增强剂NOB或HIF1A激活剂DMOG可保护小鼠免受心肌IRI损伤，而在内皮特异性缺失的小鼠中这种保护作用消失。ANGPTL4能够克服内皮缺陷，并在内皮特异性缺失或对照小鼠的心肌IRI期间显示出保护作用。对接受非心脏手术的患者进行强光治疗后，其血浆中ANGPTL4水平升高，肌钙蛋白水平降低。
我们的研究表明，只有PER2/HIF1A下游靶点ANGPTL4能够克服内皮缺陷。此外，我们发现对非心脏手术后的患者进行强光治疗可用于提高内皮保护因子ANGPTL4的血浆水平，并降低肌钙蛋白水平，肌钙蛋白是非心脏手术中心肌损伤（MINS）的一个指标。需要对更大、更多样化的人类队列进行进一步研究并进行长期随访，以验证这些发现并开发靶向治疗方法。
