Mitoquinone ameliorates pressure overload-induced cardiac fibrosis and left ventricular dysfunction in mice

Abstract

Increasing evidence indicates that mitochondrial-associated redox signaling contributes to the pathophysiology of heart failure (HF). The mitochondrial-targeted antioxidant, mitoquinone (MitoQ), is capable of modifying mitochondrial signaling and has shown beneficial effects on HF-dependent mitochondrial dysfunction. However, the potential therapeutic impact of MitoQ-based mitochondrial therapies for HF in response to pressure overload is reliant upon demonstration of improved cardiac contractile function and suppression of deleterious cardiac remodeling. Using a new (patho)physiologically relevant model of pressure overload-induced HF we tested the hypothesis that MitoQ is capable of ameliorating cardiac contractile dysfunction and suppressing fibrosis. To test this C57BL/6J mice were subjected to left ventricular (LV) pressure overload by ascending aortic constriction (AAC) followed by MitoQ treatment (2 µmol) for 7 consecutive days. Doppler echocardiography showed that AAC caused severe LV dysfunction and hypertrophic remodeling. MitoQ attenuated pressure overload-induced apoptosis, hypertrophic remodeling, fibrosis and LV dysfunction. Profibrogenic transforming growth factor-β1 (TGF-β1) and NADPH oxidase 4 (NOX4, a major modulator of fibrosis related redox signaling) expression increased markedly after AAC. MitoQ blunted TGF-β1 and NOX4 upregulation and the downstream ACC-dependent fibrotic gene expressions. In addition, MitoQ prevented Nrf2 downregulation and activation of TGF-β1-mediated profibrogenic signaling in cardiac fibroblasts (CF). Finally, MitoQ ameliorated the dysregulation of cardiac remodeling-associated long noncoding RNAs (lncRNAs) in AAC myocardium, phenylephrine-treated cardiomyocytes, and TGF-β1-treated CF. The present study demonstrates for the first time that MitoQ improves cardiac hypertrophic remodeling, fibrosis, LV dysfunction and dysregulation of lncRNAs in pressure overload hearts, by inhibiting the interplay between TGF-β1 and mitochondrial associated redox signaling.

Angiotensin II Type I Receptor Antagonism Attenuates Nicotine-Induced Cardiac Remodeling, Dysfunction, and Aggravation of Myocardial Ischemia-Reperfusion Injury in Rats

“…Mitochondrial ROS is also similarly important for pathogenesis of adverse cardiac remodeling and dysfunction. Studies have shown that mitochondria-targeted antioxidants ameliorated cardiac remodeling and functional defects in animal models of pressure-overload induced hypertrophy and diabetes (Ni et al, 2016;Goh et al, 2019). Nicotine administration for 28 days also significantly reduced activity of SOD2 without affecting its gene expression in this study.…”

Heart Plasticity in Response to Pressure- and Volume-Overload: A Review of Findings in Compensated and Decompensated Phenotypes

“…The majority of proteins are imported into mitochondria, where they undergo folding and assembly (Smyrnias et al, 2019). Production of reactive-oxygen species in pressureoverload (ROS) (Goh et al, 2019) promotes mitochondrial protein misfolding, dysfunction, and a perpetual cycle of progressively worsening mitochondrial damage (Smyrnias et al, 2019). A major source of ROS production are monoamine oxidases (MAOs), and in particular MAO-A (Kaludercic et al, 2014).…”

Cyclovirobuxine D protects against diabetic cardiomyopathy by activating Nrf2-mediated antioxidant responses

“…keap1 and subsequently translocated to the nucleus, which activates downstream defence genes, such as NAD(P) H: quinone oxidoreductase 1 (NQO-1) and peroxide enzyme 1 (Prdx1) 11,12 . As oxidative stress is a common pathogenesis of metabolic diseases, some pharmacological activators of Nrf2, such as mitoquinone 13,14 , bardoxolone methyl 15 , and sulforaphane 16 , have shown beneficial therapeutic potential. However, off-target side effects also were observed because of the unselective activity of Nrf2 [17][18][19] .…”