Antioxidant-based therapies for angiotensin II-associated cardiovascular diseases

Abstract

Cardiovascular diseases, including hypertension and heart failure, are associated with activation of the renin-angiotensin system (RAS) and increased circulating and tissue levels of ANG II, a primary effector peptide of the RAS. Through its actions on various cell types and organ systems, ANG II contributes to the pathogenesis of cardiovascular diseases by inducing cardiac and vascular hypertrophy, vasoconstriction, sodium and water reabsorption in kidneys, sympathoexcitation, and activation of the immune system. Cardiovascular research over the past 15-20 years has clearly implicated an important role for elevated levels of reactive oxygen species (ROS) in mediating these pathophysiological actions of ANG II. As such, the use of antioxidants, to reduce the elevated levels of ROS, as potential therapies for various ANG II-associated cardiovascular diseases has been intensely investigated. Although some antioxidant-based therapies have shown therapeutic impact in animal models of cardiovascular disease and in human patients, others have failed. In this review, we discuss the benefits and limitations of recent strategies, including gene therapy, dietary sources, low-molecular-weight free radical scavengers, polyethylene glycol conjugation, and nanomedicine-based technologies, which are designed to deliver antioxidants for the improved treatment of cardiovascular diseases. Although much work has been completed, additional research focusing on developing specific antioxidant molecules or proteins and identifying the ideal in vivo delivery system for such antioxidants is necessary before the use of antioxidant-based therapies for cardiovascular diseases become a clinical reality.

Keywords: angiotensin; antioxidants; cardiovascular disease; free radical scavengers; oxidative stress; therapy.

Fig. 1.

Schematic of CuZnSOD nanozyme in which negatively charged CuZnSOD protein (green) electrostatically interacts with positively charged poly-l-lysine-poly-ethylene glycol (PLL-PEG; blue/red lines). CuZnSOD nanozyme retains neutral charge at physiological pH and, as depicted here, our second-generation nanozyme is synthesized with increased stability due to either reducible or nonreducible cross-link bonds (orange circle) between PLL polymer chains.

Fig. 2.

Representative electron paramagnetic resonance (EPR) spectrum and corresponding bar graph showing the O₂˙⁻-sensitive 1-hydroxy-3-methoxycarbonyl-2,2,5,5-tetramethylpyrrolidine (CMH) spin probe spectrum amplitude in arbitrary units (AU). In all samples, O₂˙⁻ was generated in a cell-free system by hypoxanthine (HX) and xanthine oxidase (XO). Levels of O₂˙⁻ were measured using CMH and a Bruker Biospin eScan Spectrometer. Superoxide levels were similarly reduced in samples containing free CuZnSOD protein, non-cross-linked CuZnSOD nanozyme, reducible cross-linked nanozyme, and nonreducible cross-linked nanozyme; thus, indicating that CuZnSOD nanozyme retains enzymatic activity.

Fig. 3.

Summary schematic illustrating different experimental strategies to deliver antioxidants in vivo for the improved treatment of cardiovascular diseases associated with aberrant ANG II-induced elevation in reactive oxygen species (ROS), such as hypertension, heart failure, and stroke. These strategies, including gene therapy, dietary sources, low-molecular-weight antioxidant mimetics, PEGylation of antioxidant proteins, and antioxidant-based nanomedicines, have been shown to inhibit elevated ROS levels and improve cardiovascular function.