Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy.
Chair of Pharmacology, Section of Medicine, University of Fribourg, Fribourg, Switzerland.
Physiol Rev. 2023 Jan 1;103(1):31-276. doi: 10.1152/physrev.00028.2021. Epub 2022 Apr 18.
Over the last two decades, hydrogen sulfide (HS) has emerged as an endogenous regulator of a broad range of physiological functions. HS belongs to the class of molecules known as gasotransmitters, which typically include nitric oxide (NO) and carbon monoxide (CO). Three enzymes are recognized as endogenous sources of HS in various cells and tissues: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MST). The present article reviews the regulation of these enzymes as well as the pathways of their enzymatic and nonenzymatic degradation and elimination. The multiple interactions of HS with other labile endogenous molecules (e.g., NO) and reactive oxygen species are also outlined. Next, the various biological targets and signaling pathways are outlined, with special reference to HS or oxidative posttranscriptional modification (persulfidation or sulfhydration) of proteins and the effect of HS on various channels and intracellular second messenger pathways, the regulation of gene transcription and translation, and the regulation of cellular bioenergetics and metabolism. The pharmacological and molecular tools currently available to study HS physiology are also reviewed, including their utility and limitations. In subsequent sections, the role of HS in the regulation of various physiological and cellular functions is reviewed, including the regulation of membrane potential, endo- and exocytosis, regulation of various cell organelles (endoplasmic reticulum, Golgi, mitochondria), regulation of cell movement, cell cycle, cell differentiation, and physiological aspects of regulated cell death. Next, the physiological roles of HS in various cell types and organ systems are overviewed, including the role of HS in red blood cells, immune cells, the central and peripheral nervous systems (with focus on neuronal transmission, learning, and memory formation), and regulation of vascular function (including angiogenesis as well as its specialized roles in the cerebrovascular, renal, and pulmonary vascular beds) and the role of HS in the regulation of special senses, vision, hearing, taste and smell, and pain-sensing. Finally, the roles of HS in the regulation of various organ functions (lung, heart, liver, kidney, urogenital organs, reproductive system, bone and cartilage, skeletal muscle, and endocrine organs) are presented, with a focus on physiology (including physiological aging) but also extending to some common pathophysiological conditions. From these data, a wide array of significant roles of HS in the physiological regulation of all organ functions emerges and the characteristic bell-shaped biphasic effects of HS are highlighted. In addition, key pathophysiological aspects, debated areas, and future research and translational areas are identified.
在过去的二十年中，硫化氢 (HS) 已成为广泛生理功能的内源性调节剂。HS 属于被称为气体递质的分子类别，通常包括一氧化氮 (NO) 和一氧化碳 (CO)。三种酶被认为是各种细胞和组织中 HS 的内源性来源：胱硫醚 γ-裂解酶 (CSE)、胱硫醚 β-合酶 (CBS) 和 3-巯基丙酮酸硫转移酶 (3-MST)。本文综述了这些酶的调节以及它们的酶促和非酶促降解和消除途径。还概述了 HS 与其他不稳定内源性分子 (例如，NO) 和活性氧物质的多种相互作用。接下来，概述了各种生物靶标和信号通路，特别提到了 HS 或蛋白质的氧化转录后修饰 (persulfidation 或 sulfhydration) 以及 HS 对各种通道和细胞内第二信使途径、基因转录和翻译的调节以及细胞生物能学和代谢的调节。还回顾了目前可用于研究 HS 生理学的药理学和分子工具，包括它们的用途和局限性。在随后的章节中，综述了 HS 在调节各种生理和细胞功能中的作用，包括膜电位的调节、内和外分泌、各种细胞细胞器 (内质网、高尔基体、线粒体) 的调节、细胞运动、细胞周期、细胞分化和调节细胞死亡的生理方面。接下来，概述了 HS 在各种细胞类型和器官系统中的生理作用，包括 HS 在红细胞、免疫细胞、中枢和外周神经系统 (重点是神经元传递、学习和记忆形成) 以及血管功能调节 (包括血管生成以及其在脑血管、肾和肺血管床中的特殊作用) 和 HS 在调节特殊感觉、视力、听力、味觉和嗅觉以及疼痛感觉中的作用。最后，介绍了 HS 在调节各种器官功能 (肺、心脏、肝脏、肾脏、泌尿生殖器官、生殖系统、骨骼和软骨、骨骼肌和内分泌器官) 中的作用，重点是生理学 (包括生理衰老)，但也扩展到一些常见的病理生理状况。从这些数据中，可以看出 HS 在所有器官功能的生理调节中具有广泛的重要作用，并突出了 HS 的特征双相钟形效应。此外，还确定了关键的病理生理方面、有争议的领域以及未来的研究和转化领域。
