Advances in pathogenesis and treatment of vascular endothelial injury-related diseases mediated by mitochondrial abnormality

Abstract

Vascular endothelial cells, serving as a barrier between blood and the arterial wall, play a crucial role in the early stages of the development of atherosclerosis, cardiovascular diseases (CVDs), and Alzheimer's disease (AD). Mitochondria, known as the powerhouses of the cell, are not only involved in energy production but also regulate key biological processes in vascular endothelial cells, including redox signaling, cellular aging, calcium homeostasis, angiogenesis, apoptosis, and inflammatory responses. The mitochondrial quality control (MQC) system is essential for maintaining mitochondrial homeostasis. Current research indicates that mitochondrial dysfunction is a significant driver of endothelial injury and CVDs. This article provides a comprehensive overview of the causes of endothelial injury in CVDs, ischemic stroke in cerebrovascular diseases, and AD, elucidating the roles and mechanisms of mitochondria in these conditions, and aims to develop more effective therapeutic strategies. Additionally, the article offers treatment strategies for cardiovascular and cerebrovascular diseases, including the use of clinical drugs, antioxidants, stem cell therapy, and specific polyphenols, providing new insights and methods for the clinical diagnosis and treatment of related vascular injuries to improve patient prognosis and quality of life. Future research should delve deeper into the molecular and mechanistic links between mitochondrial abnormalities and endothelial injury, and explore how to regulate mitochondrial function to prevent and treat CVDs.

Keywords: Alzheimer’s disease; cardiovascular diseases; endothelial cell injury; ischemic stroke; mitochondria abnormality; treatment.

FIGURE 1

Mitochondria affect endothelial cell function and metabolism. (A) Mitochondria regulate several key biological processes in the endothelial cells, such as energy production, angiogenesis, coagulation, apoptosis, inflammation response, calcium homeostasis, cellular senescence and redox signaling. Copyright 2021, Reprinted with from permission from Ivyspring International Publisher (Chang et al., 2021). (B) MQC coordinates various processes including fusion, division, mitotic phagocytosis and mitochondria-controlled cell death under physiological conditions and I/R injury. Mitochondrial dysfunction in quality-control processes is the main mechanism of cardiac I/R injury. Copyright 2020, Reprinted with from permission from Elsevier B.V. (Wang and Zhou, 2020). (C) Overview of mitochondrial metabolism in endothelial cells. In endothelial cells, the mitochondrial respiratory chain complexes I-IV create a proton gradient across the inner mitochondrial membrane (IMM), which powers adenosine triphosphate (ATP) production by ATP synthase (Complex V). Electrons from NADH and FADH2 flow through Complexes I and II, then to Complex III via ubiquinol (CoQ). Electrons are passed from Complex III to Complex IV by cytochrome c, reducing oxygen to water. This electron flow is coupled with proton (H⁺) transfer, creating an electrochemical gradient (ψm). Protons re-enter the matrix through Complex V to produce ATP, and uncoupling proteins and mitoK ATP channels allow protons to bypass this process, reducing reactive oxygen species (ROS) formation. PON2: paraoxonase 2, NOX4: nicotinamide adenine dinucleotide phosphate oxidase 4, UCP2: uncoupling protein 2. Copyright 2022, Reprinted with from permission from Nature Publishing Group (Sun et al., 2022).

FIGURE 2

Pathogenesis and therapeutic strategies of cardiovascular diseases based on mitochondrial abnormality. (A) The role of mitochondrial reactive oxygen species (ROS) in ischemia-reperfusion (I/R) injury is multifaceted. When cells experience ischemia-induced hypoxia, it leads to a halt in the electron transport chain (ETC) within the inner mitochondrial membrane (IMM), which in turn triggers the production of ROS. The reoxygenation phase is further exacerbated by the heightened activity of monoamine oxidases (MAOs), NADPH oxidase, and p66shc, as well as by structural alterations in xanthine oxidase and the uncoupling of nitric oxide (NO) synthase, all of which contribute to an increase in ROS levels. Copyright 2016, Reprinted with from permission from Hindawi Publishing Group (Muntean et al., 2016). (B,C) Empagliflozin attenuates myocardial microvascular damage by mediating mitochondrial fission. (B) Empagliflozin diminishes diabetic-induced mitochondrial fragmentation and regulated the balance of proteins responsible for mitochondrial fission and fusion. Co-localization of Drp1 and mitochondria. The boxed area under each micrograph represents the amplifification of the white square. More Drp1 was located on fragmented mitochondria, while empagliflozin reduced Drp1 migration ontomitochondria. Copyright 2017, Reprinted with from permission from Elsevier B.V (Zhou et al., 2018). (C) The diagram illustrates the protective mechanisms by which empagliflozin shields the microvasculature from damage in diabetes. Empagliflozin initiates its protective effect by stimulating the AMPK signaling pathway, which is regulated by the balance of AMP to ATP ratios. Once activated, AMPK influences the posttranscriptional phosphorylation of Drp1 at specific sites, Ser616 and Ser637. The modification inhibits Drp1’s capacity to migrate to the mitochondria, thereby impairing mitochondrial fission. The resulting reduction in mitochondrial fission slows down cellular aging and maintains the integrity of the endothelial barrier and permeability by reducing the excess production of ROS. (D) Endothelial-specific overexpression of PRDX2 alleviated cardiac microvascular injury and improved cardiac function after long-term diabetes. Isoliquitigenin could inhibit mitochondrial iron toxicity through PRDX2-MFN2-ACS14 pathway, thus effectively protecting cardiac microvessels in diabetic patients. The cardiac microvascular density was indicated by the number of CD31-positive microvessels (green), and microvascular perfusion was indicated by the ratio of FITC-positive microvessels (green) to CD31-positive microvessels (red). Scale bars = 40 mm. Copyright 2023, Reprinted with from permission from American Diabetes Association (Chen et al., 2023). (E) Utilizing lipophilic cations to selectively deliver MitoQ towards mitochondria within cells to target mitochondria. The accumulation of lipophilic cations within the mitochondria is facilitated by the mitochondrial membrane potential. These cations can readily traverse lipid bilayers due to the delocalization of their positive charge over a broad area, which enhances their permeability. Copyright 2007, Reprinted with from permission from International Scientific Literature Inc. (Milagros Rocha and Victor, 2007).