This article is part of the Innovation and Discovery in Cardiovascular Biology special issue. The ACS journal Pharmacology and Translational Science is pleased to be publishing a Special Issue focused on Innovations and Discovery in Cardiovascular Biology. Despite tremendous advances in the detection and treatment of cardiovascular diseases, as a group these pathologies remain the number one cause of global death, accounting for approximately 17.9 million deaths in 2016; nearly one-third of all deaths worldwide.(1) Idiopathic and resistant hypertension remain significant underlying origins of cardiovascular disease and stroke, and yet the genetic, environmental, and pathophysiological underpinnings of dysfunctional blood pressure regulation remain murky. Large-scale clinical studies have made some progress toward revealing common predictive biomarkers or genetic variants associated with cardiovascular disease, so that clinical care and management of at-risk individuals is occurring earlier in life. However, our therapeutic arsenals have not expanded in a way that enables us to achieve our vision of personalized or bench-to-bedside medicine. In addition, there remains broad sex bias toward adult males in clinical studies and genome-wide association studies, thereby undermining the ultimate success of putative diagnostics and therapeutics for the general population.(2) Therefore, we focus this issue of Pharmacology and Translational Science on the publication of primary research discoveries in areas broadly related to cardiovascular disease. We specifically solicited submissions that used innovative technological approaches and interdisciplinary methodologies to elucidate mechanistic pathways underlying cardiovascular pathophysiology. In keeping with the scope of the journal, we were excited to receive submissions that focus on therapeutic strategies and targets. Collectively, this special issue on Innovations and Discovery in Cardiovascular Biology has been successful in coalescing reviews and primary research articles that pave the way toward new diagnostics and therapeutics as well as an improved understanding of the integrative physiology that underlies the world’s most common and deadly disease. Two separate articles are focused on revealing novel molecular pathways associated with cardiac dysfunction. The irreversible death of cardiomyocytes following an ischemic event is mediated through both apoptosis and necrosis, but recent studies suggest that necrosis may be a reversible event. Therefore, Cheng et al.(3) used a genome-wide RNAi screen in human muscle cells to identify key pathways involved in calcium-induced necrosis. They discovered multiple molecular pathways, encompassing several druggable enzymes, that either enhance or inhibit cardiomyocyte necrosis, thereby offering a rich data set of clinically relevant targets for cardiac ischemia. Zhang et al.(4) tackled the complex problem of cardiotoxicity and cardiac failure following chemotherapy by performing a small-scale clinical study aimed at discovering better predictive markers of cardiotoxicity in patients treated with chemotherapy. Using nanotrap fractionation and mass spectometry of plasma, the group was able to enrich for plasma peptides produced by cathepsin B cleavage. They discovered a plasma peptide fragment from serum amyloid A1 which could effectively serve as a sensitive, precise, and minimally invasive biomarker to detect chemotherapy-induced cardiotoxicity. Together, these studies exemplify how sophisticated biochemical technologies (nanotrap fractionation) and innovative screening approaches (RNAi screens) can be harnessed to reveal previously unrecognized paths for precision diagnosis of cardiotoxicity or new molecular targets for treatment of cardiac ischemia. The study by Igreja and colleagues(5) uses the preclinical, aged spontaneously hypertensive rat (SHR) model to explore the therapeutic potential of a relatively new dopamine β-hydroxylase inhibitor, zamicastat, as a possible therapeutic strategy to reduce overactivity of the sympathetic nervous system—a clinical condition that is commonly associated with essential hypertension and congestive heart failure. Consistent with early stage clinical trials, the authors found that a daily dosage of zamicastat for 9 weeks significantly decreased norepinephrine levels and improved overall cardiometabolic health in the aged SHR rats compared to nonhypertensive controls. These positive outcomes should bolster current efforts at therapeutically targeting sympathetic overactivity in order to alleviate hypertension and its many cardiovascular comorbidities. Two exciting research articles focus their efforts on therapeutically targeting the vascular system. Kofler et al.(6) capitalize on the robust physiological angiogenesis associated with corpus luteal formation following ovulation to test and characterize the effects of Jagged-specific Notch inhibition on vascular growth and pericyte recruitment. Their studies reveal remarkable differences between the vascular effects of Notch inhibition during normal ovulation compared to hyperstimulated ovulation—a condition that is present in women undergoing assisted reproductive technologies. Overall, the study highlights the inherent heterogeneity of the vasculature, and the variability that this heterogeneity imparts on therapeutic compounds and their anticipated actions. Tacconi et al.(7) used a mouse model of colitis to test the efficacy of a novel form of vascular endothelial growth factor C (VEGFC) that is fused to the F8 antibody, thereby delivering a potent lymphangiogenic signal to sites of inflammation. Systemic treatment with this new therapeutic tool expectedly stimulated profound lymphangiogenesis and further culminated in a significant reduction in inflammation and associated inflammatory cells and markers. These studies serve to underscore the strong interdependence of peripheral organ function on its invested vasculature, while also providing deeper mechanistic insights and novel therapeutic strategies into two of the most studied and therapeutically tractable vascular signaling pathways: VEGF and NOTCH signaling. The special issue also includes two lymphatic-themed review articles, representing a largely understudied vascular system compared to the blood vasculature. Indeed, authors Sestito and Thomas(8) bring forth a highly innovative and comprehensive review to introduce readers to the unique properties of lymphatic vessels which render them desirable to modulate therapeutically, but at the same time, present distinct challenges for targeted drug delivery. The authors expand on the potential of biomaterials for enhancing lymphangiogenesis in the periphery as well as in lymph nodes. Ultimately, given the predominate immunomodulatory functions of the lymphatic vasculature, their specific targeting with biomaterials and nanoparticles could significantly expand the clinical value of this vascular highway beyond the cardiovascular system and into a myriad of disease conditions that require the fine-tuning of immune regulation. The review article by Trincot and Caron(9) also addresses the lymphatic system, but draws special attention to our lack of appreciation for the fundamental differences in lymphatic vascular biology that are imparted by biological sex. Indeed, the prevalence of biomedical knowledge, from basic foundational studies to large scale clinical trials, is largely biased toward the male sex. Studies in the lymphatic vascular system are no exception, but considering the preponderance of women affected by lymphatic disorders compared to men, a focused attention to sex differences in lymphatic vascular biology, as summarized in the review, is certainly an area of cardiovascular biology worth pursuing on a large scale. Finally, we are excited to publish one of our Drug Discovery Series of articles—insightful and personal commentary articles from pioneering drug discovery leaders about their experiences in developing a particular therapeutic, from the bench to the bedside. This article by Dr. Lotte Knudsen(10) chronicles the development of liraglutide, a glucagon-like peptide-1 analogue, designed for treatment of diabetes and obesity, with beneficial effects on atherosclerosis protection. We hope that readers of ACS Pharmacology and Translational Science will enjoy learning about these remarkable and insightful discoveries in the field of cardiovascular biology. The special issue provides the full spectrum of bench-to-bedside translational research: from the discovery of predictive biomarkers of disease to target discovery and mechanistic preclinical validation and culminating in drug delivery modalities and drug launches. There remains much work to be done to combat cardiovascular disease, and the articles in this special issue are certain to make impactful and lasting contributions to our worldwide scientific efforts. Views expressed in this editorial are those of the author and not necessarily the views of the ACS. The author wishes to thank and congratulate all coauthors of the Special Issue for their innovative and groundbreaking contributions. The author acknowledges grant support from NIH NIDDK099156, NIH NHLBI HL129086. This article references 10 other publications.

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心血管生物学的创新与发现

本文是 心血管生物学的创新与发现特刊。ACS杂志《药理学与转化科学》很高兴出版《心血管生物学的创新与发现》特刊。尽管在心血管疾病的检测和治疗方面取得了巨大进步，但作为一组，这些病理仍然是全球死亡的第一大原因，2016年约有1790万例死亡。全世界将近三分之一的死亡病例。（1）特发性和耐药性高血压仍然是心血管疾病和中风的重要根本原因，但血压调节异常的遗传，环境和病理生理基础仍然模糊。大规模临床研究在揭示与心血管疾病相关的常见预测性生物标志物或遗传变异方面取得了一些进展，因此高危人群的临床护理和管理发生在生命的早期。但是，我们的治疗武库并未以能够使我们实现个性化或从台到床医疗的愿景扩展。此外，在临床研究和全基因组关联研究中，成年男性仍然存在广泛的性别偏见，从而破坏了一般人群推定的诊断方法和治疗方法的最终成功。（2）因此，我们关注这一问题药理学与转化科学关于与心血管疾病广泛相关领域的主要研究发现的发表。我们特别征集了使用创新技术方法和跨学科方法论来阐明心血管病理生理学机制的论文。与期刊的范围保持一致，我们很高兴收到专注于治疗策略和目标的投稿。总的来说，本期《心血管生物学的创新与发现》特刊成功地汇集了评论和主要研究文章，为新的诊断和治疗方法铺平了道路，并加深了对作为全球最常见和致命疾病基础的综合生理学的理解。两篇不同的文章集中在揭示与心脏功能障碍相关的新型分子途径。缺血事件后心肌细胞的不可逆死亡是通过凋亡和坏死介导的，但最近的研究表明坏死可能是可逆事件。因此，Cheng等人（3）在人类肌肉细胞中使用了全基因组的RNAi筛查方法来鉴定与钙诱导的坏死有关的关键途径。他们发现了包含多种可药物化酶的多种分子途径，这些途径可增强或抑制心肌细胞坏死，从而为心脏病的临床相关靶标提供了丰富的数据集。张等。（4）通过进行旨在发现化疗患者更好的心脏毒性预测指标的小型临床研究，解决了化疗后心脏毒性和心力衰竭的复杂问题。使用血浆的纳阱捕集分离和质谱分析，该小组能够富集组织蛋白酶B裂解产生的血浆肽。他们发现了来自血清淀粉样蛋白A1的血浆肽片段，可以有效地用作敏感，精确和微创的生物标志物，以检测化疗引起的心脏毒性。一起，这些研究例证了如何利用复杂的生化技术（纳米阱分级分离）和创新的筛查方法（RNAi筛查）来揭示以前无法识别的精确诊断心脏毒性的途径或用于治疗心肌缺血的新分子靶标。Igreja及其同事（5）的研究使用了临床前的老年自发性高血压大鼠（SHR）模型，探索了一种相对较新的多巴胺β-羟化酶抑制剂za​​micastat的治疗潜力，作为减少交感神经过度活跃的一种可能的治疗策略。系统—一种通常与原发性高血压和充血性心力衰竭相关的临床疾病。与早期临床试验一致，作者发现，与非高血压对照组相比，每天服用Zamicastat 9周的剂量可显着降低老年SHR大鼠的去甲肾上腺素水平，并改善整体心脏代谢健康。这些积极的结果应加强目前在治疗上针对交感神经过度活动的努力，以减轻高血压及其许多心血管疾病的合并症。两项激动人心的研究文章将他们的精力集中在针对血管系统的治疗上。Kofler等人（6）利用与排卵后黄体形成相关的强大生理血管生成来测试并表征锯齿状Notch抑制对血管生长和周细胞募集的影响。他们的研究显示，在正常排卵期间，Notch抑制的血管作用与过度刺激排卵之间存在显着差异，这种情况存在于接受辅助生殖技术的女性中。总体而言，该研究突出了脉管系统固有的异质性，以及这种异质性赋予治疗性化合物及其预期作用的可变性。Tacconi等人（7）使用了一种结肠炎小鼠模型来测试与F8抗体融合的新型形式的血管内皮生长因子C（VEGFC）的功效，从而向炎症部位传递有效的淋巴管生成信号。用这种新的治疗工具进行的全身治疗有望刺激大量的淋巴管生成，并进一步导致炎症以及相关炎症细胞和标志物的显着减少。这些研究旨在强调外周器官功能与其所投资的脉管系统之间的强烈相互依赖性，同时还为研究最深入和可治疗的两种血管信号通路（VEGF和NOTCH信号通路）提供了更深的机理见解和新颖的治疗策略。特刊还包括两篇以淋巴为主题的评论文章，与血管系统相比，它们代表的血管系统研究不足。的确，作者Sestito和Thomas（8）提出了高度创新和全面的综述，向读者介绍了淋巴管的独特特性，这使它们成为理想的治疗性调节药物，但同时，也对靶向药物递送提出了独特的挑战。作者扩展了生物材料增强外周和淋巴结淋巴管生成的潜力。最终，鉴于淋巴管系统的主要免疫调节功能，它们对生物材料和纳米颗粒的特异性靶向作用可大大扩展该血管通路的临床价值，超越心血管系统，并扩展到许多疾病状态，需要对免疫调节进行微调。Trincot和Caron（9）发表的评论文章还谈到了淋巴系统，但特别引起我们注意的是，我们对生物性别所赋予的淋巴管生物学的根本差异缺乏理解。实际上，从基础研究到大规模临床试验，生物医学知识的普及在很大程度上偏向男性。淋巴管系统的研究也不例外，但是考虑到淋巴失调患者比男性多，因此，正如本综述所总结的那样，关注淋巴管生物学中的性别差异无疑是心血管生物学领域中值得追求的领域。大范围上。最后，我们很高兴发表我们的《药物发现系列》中的一篇文章-先锋药物发现领导者提供的有见地的个人评论文章，介绍了他们从实验台到床边开发特定疗法的经验。Lotte Knudsen博士（10）的这篇文章记载了利拉鲁肽的发展，利拉鲁肽是一种胰高血糖素样肽1类似物，旨在治疗糖尿病和肥胖症，对保护动脉粥样硬化具有有益的作用。我们希望ACS的读者药理学与转化科学将乐于了解心血管生物学领域的这些非凡而有见地的发现。特刊提供了从台到床的所有翻译研究的全貌：从发现疾病的预测性生物标志物到靶向发现和机制的临床前验证，并最终达到药物输送方式和药物发布的目的。在抗击心血管疾病方面还有许多工作要做，本期特刊中的文章必将为我们在全球范围内的科学努力做出有意义而持久的贡献。本社论中表达的观点只是作者的观点，不一定是ACS的观点。作者要感谢并祝贺《特刊》的所有合著者所做的创新和开创性的贡献。作者感谢NIH NIDDK099156，NIH NHLBI HL129086的资助。本文引用了其他10个出版物。