Oxidative stress in cardiac hypertrophy: From molecular mechanisms to novel therapeutic targets

• Published in: Free radical biology & medicine 2021-04, Vol.166, p.297-312
• Main Authors: Ramachandra, Chrishan J.A., Cong, Shuo, Chan, Xavier, Yap, En Ping, Yu, Fan, Hausenloy, Derek J.
• Format: Article
• Language: English
• Subjects: Antioxidants; Cardiac hypertrophy; Diabetes; Drug repurposing; Hypertension; Inflammation; Oxidative stress; Reactive oxygen species (ROS)
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2021.02.040

When faced with increased workload the heart undergoes remodelling, where it increases its muscle mass in an attempt to preserve normal function. This is referred to as cardiac hypertrophy and if sustained, can lead to impaired contractile function. Experimental evidence supports oxidative stress as a critical inducer of both genetic and acquired forms of cardiac hypertrophy, a finding which is reinforced by elevated levels of circulating oxidative stress markers in patients with cardiac hypertrophy. These observations formed the basis for using antioxidants as a therapeutic means to attenuate cardiac hypertrophy and improve clinical outcomes. However, the use of antioxidant therapies in the clinical setting has been associated with inconsistent results, despite antioxidants having been shown to exert protection in several animal models of cardiac hypertrophy. This has forced us to revaluate the mechanisms, both upstream and downstream of oxidative stress, where recent studies demonstrate that apart from conventional mediators of oxidative stress, metabolic disturbances, mitochondrial dysfunction and inflammation as well as dysregulated autophagy and protein homeostasis contribute to disease pathophysiology through mechanisms involving oxidative stress. Importantly, novel therapeutic targets have been identified to counteract oxidative stress and attenuate cardiac hypertrophy but more interestingly, the repurposing of drugs commonly used to treat metabolic disorders, hypertension, peripheral vascular disease, sleep disorders and arthritis have also been shown to improve cardiac function through suppression of oxidative stress. Here, we review the latest literature on these novel mechanisms and intervention strategies with the aim of better understanding the complexities of oxidative stress for more precise targeted therapeutic approaches to prevent cardiac hypertrophy. Schematic illustration of the pathways central to oxidative stress-induced cardiac hypertrophy. [Display omitted] •Oxidative stress is a critical inducer of pathological cardiac hypertrophy.•Metabolic, mitochondrial and inflammatory pathways are mediators of oxidative stress.•Antioxidant therapies have been unsuccessful in clinical settings.•Drug repurposing could be a prospective strategy for improving clinical outcomes.