Abstract
Background and AimsNuclear factor E2-related factor 2 (Nrf2) appears to be an attractive therapeutic target for the treatment of cardiac disease. We investigated whether a synthetic triterpenoid derivative of dihydro-CDDO-trifluoroethylamide (dh404), a novel Nrf2 activator, protects against pathological cardiac responses to hemodynamic stress in mice.MethodsCardiac maladaptive remodeling and dysfunction were established by transverse aortic constriction (TAC) in mice. Hypertrophic growth of rat neonatal cardiomyocytes was induced by angiotensin II (Ang II). Cell death of rat neonatal cardiomyocytes was induced with hydrogen peroxide (H2O2). Cellular proliferation of rat neonatal cardiac fibroblasts was induced by Ang II, norepinephrine (NE) and phenylephrine (PE). Protein expression was assessed by immunochemical staining and Western blots. Gene expression was determined by real time reverse transcription-polymerase chain reaction (Q-PCR).ResultsTAC suppressed myocardial Nrf2 expression, increased myocardial 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine levels, and induced cardiac hypertrophy, fibrosis and apoptosis, and overt heart failure and death in mice. Administration of dh404 inhibited the pathological cardiac remodeling and dysfunction, and reduced the mortality. Moreover, dhd404 elevated myocardial levels of Nrf2 and Nrf2 nuclear translocation with a dramatic suppression of the oxidative stress in the heart. Dh404 inhibited hypertrophic growth and death in primary culture of rat neonatal cardiomyocytes and suppressed proliferation in primary culture of rat neonatal cardiac fibroblasts. However, these effects of dh404 were blunted by knocking down of Nrf2.ConclusionThese findings demonstrate that dh404 prevents pathological cardiac remodeling and dysfunction by activating Nrf2, indicating a therapeutic potential of dh404 for cardiac disease.
Highlights
Heart failure is the frequent consequence of sustained, abnormal neurohormonal and mechanical stress and remains a leading cause of death worldwide [1]
Our results indicate that targeting Nuclear factor E2-related factor 2 (Nrf2) by dh404 has significant potential to be a novel therapeutic approach for the prevention of adverse myocardial remodeling that leads to heart failure
To study a therapeutic potential of dh404 for the pathological cardiac remodeling and heart failure, we examined the effect of dh404 on myocardial hypertrophy (Figure 1, Table 1), fibrosis (Figure 2) and apoptosis (Figure 3), cardiac dysfunction, and mortality (Figure 1, Table 1) in mice after 4 wk of transverse aortic constriction (TAC), a wellestablished model of pressure overload-induced pathological remodeling and dysfunction in rodents [18]
Summary
Heart failure is the frequent consequence of sustained, abnormal neurohormonal and mechanical stress and remains a leading cause of death worldwide [1] Pathological stress, such as hypertension, results in cardiac hypertrophy, myocardial apoptosis and fibrosis, altered microvascular structure, and chamber dilation, culminating in cardiac dysfunction and heart failure [2,3]. It is firmly established that oxidative stress characterized by elevated levels of reactive oxygen species (ROS) plays a causative role in the pathogenesis of cardiovascular disease [6,7,8] This being the case it is surprising that clinical trials have shown antioxidant vitamins to be ineffective or even harmful for the treatment of cardiovascular disease [9,10,11,12]. We investigated whether a synthetic triterpenoid derivative of dihydro-CDDOtrifluoroethylamide (dh404), a novel Nrf activator, protects against pathological cardiac responses to hemodynamic stress in mice
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