Abstract
Cardiac hypertrophy is the underlying cause of heart failure and is characterized by excessive oxidative stress leading to collagen deposition. Therefore, understanding the signalling mechanisms involved in excessive extracellular matrix deposition is necessary to prevent cardiac remodelling and heart failure. In this study, we hypothesized that hesperetin, a flavanone that elicits the activation of Nrf2 signalling and thereby suppresses oxidative stress, mediated pathological cardiac hypertrophy progression. A cardiac hypertrophy model was established with subcutaneous injection of isoproterenol in male Wistar rats. Oxidative stress markers, antioxidant defense status, and its upstream signalling molecules were evaluated to discover the impacts of hesperetin in ameliorating cardiac hypertrophy. Our results implicate that hesperetin pretreatment resulted in the mitigation of oxidative stress by upregulating antioxidant capacity of the heart. This curative effect might be owing to the activation of the master regulator of antioxidant defense system, known as Nrf2. Further, analysis of Nrf2 revealed that hesperetin enhances its nuclear translocation as well as the expression of its downstream targets (GCLC, NQO1, and HO-1) to boost the antioxidative status of the cells. To support this notion, in vitro studies were carried out in isoproterenol-treated H9c2 cells. Immunocytochemical analysis showed augmented nuclear localization of Nrf2 implicating the action of hesperetin at the molecular level to maintain the cellular redox homeostasis. Thus, it is conceivable that hesperetin could be a potential therapeutic candidate that enhances Nrf2 signalling and thereby ameliorates pathological cardiac remodelling.
Highlights
Cardiac hypertrophy is the heart’s response to multiple forms of stress with an adaptive increase in cardiac mass
Cardiac hypertrophy is characterized by an increase in myocardial cell size, a higher degree of sarcomeric organization, reactivation of the fetal gene program, and changes in gene transcription and translation resulting in enhanced protein synthesis [1,2,3]
Animals were divided into four groups: (1) control rats; (2) hypertrophy-induced rats; (3) rats pretreated with hesperetin and given isoproterenol 5 mg/kg body weight, subcutaneously for 7 days; and (4) rats pretreated with hesperetin
Summary
Cardiac hypertrophy is the heart’s response to multiple forms of stress with an adaptive increase in cardiac mass. Pathological hypertrophy is initially beneficial, prolonged hypertrophy leads to heart failure and sudden death [4, 5]. Pathological conditions such as hypertension and myocardial infarction can lead to hypertrophy [6]. Oxidative stress has been identified as one of the key contributing factors in the progression and development of cardiac hypertrophy [10]. Reactive oxygen species (ROS) can activate a wide variety of hypertrophy signalling kinases and transcription factors [11], and excessive ROS can lead to pathological remodelling, MMP activation, fibrosis, apoptosis, and contractile dysfunction [12]
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