Oxidative Stress & Endothelial Dysfunctions

Increased reactive oxygen species (ROS) levels induce alteration of the vascular structures and functions through inflammation, cell proliferation and migration, apoptosis, and extracellular matrix alteration.1–3 Several experimental evidences support the presence of an oxidative stress component in hypertension and atherosclerotic diseases. Indeed, a tight connection between oxidative stress and endothelial disfunction has been observed in hypertensive subjects.4–8 The major players in ROS-related alteration are NO (nitrogen monoxide) bioavailability, ONOO– (peroxynitrite ions), eNOS (endothelial Nitric Oxide Synthetase), and oxidized LDL (Ox-LDL). NO is the most important endothelial relaxing factor with potent anti-atherosclerotic properties, therefore, all the conditions causing a reduction of the NO levels lead to the initiation or acceleration of atherosclerotic processes (Figure 1).4–6,9 NO quickly reacts with ROS to generate ONOO– , which affects eNOS functioning,4,7 leading to NOS uncoupling.7,10

Figure 1. Mechanisms underlying endothelial dysfunction and the functional consequences of decreased vascular bioavailability of nitric oxide (NO). The picture was retrieved from reference number 11.

Figure 1

In this context, uncoupled eNOS contributes to the increase of ROS levels and LDL can be oxidized to Ox-LDL, corroborating the development and progression of atherosclerosis.8,9,12,13 Ox-LDLs can be internalized into endothelial cells triggering signaling pathways promoting foam cell formation, the development of fatty streaks8,9,12,13 and the up-regulation of ACE, which induces blood pressure alterations. As a matter of fact, it has been hypothesized that ox-LDL play a crucial role in the connection between dyslipidemia and hypertension.8,9,12–15 Hence, experimental evidences clearly support  that ROS-mediated oxidative stress induces deleterious effects by triggering a cascade of signals that results into endothelial disfunction promoting the progression of cardiovascular, atherosclerosis and metabolic disorders, both in human and animal models.5,8,9,16–18

References

1.            Chuang, C. Y., Degendorfer, G. & Davies, M. J. Oxidation and modification of extracellular matrix and its role in disease. Free Radical Research 48, 970–989 (2014).

2.            Eble, J. A. & de Rezende, F. F. Redox-Relevant Aspects of the Extracellular Matrix and Its Cellular Contacts via Integrins. Antioxidants & Redox Signaling 20, 1977–1993 (2014).

3.            Nikitovic, D., Corsini, E., Kouretas, D., Tsatsakis, A. & Tzanakakis, G. ROS-major mediators of extracellular matrix remodeling during tumor progression. Food and Chemical Toxicology 61, 178–186 (2013).

4.            Schulz, E., Gori, T. & Münzel, T. Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res 34, 665–673 (2011).

5.            Madamanchi, N. R., Vendrov, A. & Runge, M. S. Oxidative Stress and Vascular Disease. ATVB 25, 29–38 (2005).

6.            Togliatto, G., Lombardo, G. & Brizzi, M. F. The Future Challenge of Reactive Oxygen Species (ROS) in Hypertension: From Bench to Bed Side. IJMS 18, 1988 (2017).

7.            Incalza, M. A. et al. Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascular Pharmacology 100, 1–19 (2018).

8.            Lubrano, V. & Balzan, S. LOX-1 and ROS, inseparable factors in the process of endothelial damage. Free Radical Research 48, 841–848 (2014).

9.            Mitra, S., Goyal, T. & Mehta, J. L. Oxidized LDL, LOX-1 and Atherosclerosis. Cardiovasc Drugs Ther 25, 419–429 (2011).

10.         Potje, S. R., Grando, M. D., Chignalia, A. Z., Antoniali, C. & Bendhack, L. M. Reduced caveolae density in arteries of SHR contributes to endothelial dysfunction and ROS production. Sci Rep 9, 6696 (2019).

11.         Münzel, T., Sinning, C., Post, F., Warnholtz, A. & Schulz, E. Pathophysiology, diagnosis and prognostic implications of endothelial dysfunction. Annals of Medicine 40, 180–196 (2008).

12.         Kattoor, A. J., Kanuri, S. H. & Mehta, J. L. Role of Ox-LDL and LOX-1 in Atherogenesis. CMC 26, 1693–1700 (2019).

13.         Kattoor, A. J., Goel, A. & Mehta, J. L. LOX-1: Regulation, Signaling and Its Role in Atherosclerosis. Antioxidants 8, 218 (2019).

14.         Ferrario, C. M., Smith, R., Levy, P. & Strawn, W. The Hypertension-Lipid Connection: Insights into the Relation between Angiotensin II and Cholesterol in Atherogenesis. The American Journal of the Medical Sciences 323, 17–24 (2002).

15.         Lu, J., Mitra, S., Wang, X., Khaidakov, M. & Mehta, J. L. Oxidative Stress and Lectin-Like Ox-LDL-Receptor LOX-1 in Atherogenesis and Tumorigenesis. Antioxidants & Redox Signaling 15, 2301–2333 (2011).

16.         Dey, S., DeMazumder, D., Sidor, A., Foster, D. B. & O’Rourke, B. Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure. Circ Res 123, 356–371 (2018).

17.         Vona, R., Gambardella, L., Cittadini, C., Straface, E. & Pietraforte, D. Biomarkers of Oxidative Stress in Metabolic Syndrome and Associated Diseases. Oxidative Medicine and Cellular Longevity 2019, e8267234 (2019).

18.         Roberts, C. K. & Sindhu, K. K. Oxidative stress and metabolic syndrome. Life Sciences 84, 705–712 (2009).