Therapeutic Strategies for Oxidative Stress-Related Cardiovascular Diseases: Removal of Excess Reactive Oxygen Species in Adult Stem Cells
Therapeutic Strategies for Oxidative Stress-Related Cardiovascular Diseases: Removal of Excess Reactive Oxygen Species in Adult Stem Cells
Hyunyun Kim, Jisoo Yun, and Sang-Mo Kwon
Laboratory for Vascular Medicine and Stem Cell Biology, Convergence Stem Cell Research Center, Medical Research Institute, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
Received 13 June 2016; Accepted 17 August 2016
Academic Editor: Benjamin Pineda
Copyright © 2016 Hyunyun Kim et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Accumulating evidence indicates that acute and chronic uncontrolled overproduction of oxidative stress-related factors including reactive oxygen species (ROS) causes cardiovascular diseases (CVDs), atherosclerosis, and diabetes. Moreover ROS mediate various signaling pathways underlying vascular inflammation in ischemic tissues. With respect to stem cell-based therapy, several studies clearly indicate that modulating antioxidant production at cellular levels enhances stem/progenitor cell functionalities, including proliferation, long-term survival in ischemic tissues, and complete differentiation of transplanted cells into mature vascular cells. Recently emerging therapeutic strategies involving adult stem cells, including endothelial progenitor cells (EPCs), for treating ischemic CVDs have highlighted the need to control intracellular ROS production, because it critically affects the replicative senescence of ex vivo expanded therapeutic cells. Better understanding of the complexity of cellular ROS in stem cell biology might improve cell survival in ischemic tissues and enhance the regenerative potentials of transplanted stem/progenitor cells. In this review, we will discuss the nature and sources of ROS, drug-based therapeutic strategies for scavenging ROS, and EPC based therapeutic strategies for treating oxidative stress-related CVDs. Furthermore, we will discuss whether primed EPCs pretreated with natural ROS-scavenging compounds are crucial and promising therapeutic strategies for vascular repair.
1. Introduction
Cardiovascular diseases (CVDs), including ischemic heart disease, stroke, and hypertensive heart diseases are the leading cause of death worldwide [1]. Multiple factors of hemodynamic conditions including shear stress, laminar flow, turbulent flow, extracellular signaling proteins, including interleukins, chemokines, and cytokines, and intracellular biochemical molecules including reactive oxygen species (ROS) affect the condition of blood vessels [2–4]. High blood pressure and inflammatory reaction induced damage of blood vessels lead to hypertension, ischemic heart disease, stroke, and so forth [5, 6]. Several studies have focused on developing drug and stem cell-based therapeutic strategies for repairing ischemic blood vessels and for preserving a healthy and intact blood-endothelial barrier in patients with CVDs [7].
Recent studies have reported that uncontrolled overproduction of oxidative stress-related factors, including ROS, causes CVDs [8], atherosclerosis [9], and diabetes [10]. ROS, which are chemically reactive molecules, a spontaneously produced metabolic by-product in healthy cells, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a superoxide-producing enzyme, present in vascular endothelial and adventitial cells, is involved in ROS production [11]. Pathophysiological conditions induce an imbalance between ROS (also known as oxidants) and antioxidants. Excess ROS not only affect blood vessels, but also promote the homing of endothelial progenitor cells (EPCs) into peripheral blood [12, 13]. Accumulating evidences clearly suggest that EPCs recruited to injured ischemic sites induce neovessel formation, leading to the repair of injured tissues.
EPCs were originally identified as angiogenic progenitor cells derived from the bone marrow (BM) and blood [14], as well as other organs or tissues, including cord blood, fetal liver, and skeletal muscles. Circulating EPCs mobilized in response to ischemic repair signaling may directly reach ischemic injury sites and proliferate and differentiate in situ into mature endothelial cells (ECs) or smooth muscle cells (SMCs) [15] or may indirectly promote the proliferation or differentiation of resident ECs, resulting in the production of multiple angiogenic cytokines at ischemic sites. Many clinical studies have also reported that EPC dysfunction is closely correlated with vascular homeostasis and various CVDs, such as myocardial infarction, stroke, and hypertension [16]. Accumulating reports recently provide stem/progenitor cell-based therapy strategies using EPCs [7]. The pivotal process of these strategies can be simply explained in multiple steps as follows. First, the process of identification of target agents (...truncated)