Abstract
Oxidative stress, inflammation, and hypertension constitute a self-perpetuating vicious circle to exacerbate hypertension and subsequent hypertensive cardiac hypertrophy. NADPH oxidase (Nox) 1/4 inhibitor GKT137831 alleviates hypertensive cardiac hypertrophy in models of secondary hypertension; however, it remains unclear about its effect on hypertensive cardiac hypertrophy in models of essential hypertension. This study is aimed at determining the beneficial role of GKT137831 in hypertensive cardiac hypertrophy in spontaneously hypertensive rats (SHRs) and its mechanisms of action. Treating with GKT137831 prevented cardiac hypertrophy in SHRs. Likewise, decreasing production of reactive oxygen species (ROS) with GKT137831 reduced epidermal growth factor receptor (EGFR) activity in the left ventricle of SHRs. Additionally, EGFR inhibition also reduced ROS production in the left ventricle and blunted hypertensive cardiac hypertrophy in SHRs. Moreover, inhibition of the ROS-EGFR pathway with Nox1/4 inhibitor GKT137831 or selective EGFR inhibitor AG1478 reduced protein and mRNA levels of proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β), as well as the activities of Akt and extracellular signal-regulated kinase (ERK) 1/2 in the left ventricle of SHRs. In summary, GKT137831 prevents hypertensive cardiac hypertrophy in SHRs, Nox-deprived ROS regulated EGFR activation through positive feedback in the hypertrophic myocardium, and inhibition of the ROS-EGFR pathway mediates the protective role of GKT137831 in hypertensive cardiac hypertrophy via repressing cardiac inflammation and activation of Akt and ERK1/2. This research will provide additional details for GKT137831 to prevent hypertensive cardiac hypertrophy.
Highlights
Hypertension is one of the most common cardiovascular diseases and results in heavy burdens worldwide
These findings indicated that GKT137831 attenuated hypertensive cardiac hypertrophy independent of blood pressure
A considerable amount of studies in secondary models of hypertension indicate that reducing reactive oxygen species (ROS) production with Nox1/4 inhibitor GKT137831 attenuates hypertensive cardiac hypertrophy in rats subjected to abdominal artery constriction and angiotensin II-infused mice with cardiacspecific human Nox4 transgenic mice [5, 10]
Summary
Hypertension is one of the most common cardiovascular diseases and results in heavy burdens worldwide. Chronic pressure overload causes hypertensive cardiac hypertrophy that protects the heart in the early phase; prolonged cardiac hypertrophy leads to cardiac dysfunction, eventually promoting to the origin and development of heart failure. Inhibiting or reversing hypertensive cardiac hypertrophy will contribute to slow down or prevent the progression from hypertension to heart failure. Chronic pressure overload induces oxidative stress by producing excessive reactive oxygen species (ROS). Sustained oxidative stress has been considered a critical response to sustained high blood pressure and plays an important role in hypertensive cardiac hypertrophy [1]. A metaanalysis of seven randomized vitamin E trials does not support the beneficial role of vitamin E therapy in the Mediators of Inflammation
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