Abstract
Background: Myocardial infarction (MI) is still a major contributor to mortality worldwide, and therefore, searching for new drugs is an urgent priority. Natural products are a renewable source for medicinally and pharmacologically active molecules. The objective of this study was to explore the potential of geraniol, a monoterpene alcohol, to protect against MI. Methods: Five groups of Wister rats were used: a control group; a group treated only with geraniol; a group treated only with isoproterenol, to induce MI; and two groups pretreated with geraniol (100 or 200 mg/kg, respectively) for 14 days and challenged with isoproterenol on the 13th and 14th days. Several parameters were measured including electrocardiogram (ECG), cardiac markers, the expression of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and other downstream antioxidant enzymes, as well as the expression of phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and other downstream apoptotic and inflammatory mediators. Results: Geraniol treatment reduced the size of the infarct region, attenuated the levels of cardiac indicators, and diminished myocardial necrosis and immune cell infiltration. Geraniol treatment also activated the Keap1/Nrf2/heme oxygenase-1 (HO-1) pathway, increased antioxidant enzyme activities, modulated the PI3K/Akt/mTOR pathway, and ameliorated myocardial autophagy, inflammation, and apoptosis. Conclusion: Geraniol may possess a protective effect against MI through moderating MI-induced myocardial oxidative stress (glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione S-transferase (GST), and Keap1/Nrf2 pathway), inflammation (IL-1β, IL-6, TNF-α, and Nuclear factor-κB (NF-κB)), apoptosis (caspase-3, caspase-9, Bcl2, and Bax), and autophagy (PI3K/Akt/mTOR pathway).
Highlights
Cardiovascular diseases (CVDs) are the main cause of mortality globally, contributing to nearly 33%of the total worldwide deaths, with myocardial infarction (MI, heart attack) as a major attributor [1,2].The tissue damage associated with myocardial infraction has been ascribed to reactive oxygen species (ROS) and numerous related pathways such as tumor protein p53 (p53), AMP-activated proteinAntioxidants 2020, 9, 977; doi:10.3390/antiox9100977 www.mdpi.com/journal/antioxidantsAntioxidants 2020, 9, 977 kinase (AMPK) [3], mitogen-activated protein kinases (p38 kinase, c-Jun N-terminal kinases (JNK)and extracellular signal-regulated protein kinase (ERK1/2)) [1] and Kelch-like ECH-associated protein1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)
Within the complex autophagy signaling web, two established pathways have been extensively designated for autophagy regulation [7]; phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin and AMPK
Myocardial infarction (MI), the expression levels of phosphorylated PI3K (pPI3k), phosphorylated Akt (pAkt), and phosphorylated mTOR (pmTOR) were decreased, whereas in geraniol-pretreated animals, the levels of these phosphorylated proteins were ameliorated. These results indicate that geraniol caused the activation of PI3k/Akt in a dose-dependent manner and suggest that it may have modulated the myocardial autophagy by this mechanism
Summary
Cardiovascular diseases (CVDs) are the main cause of mortality globally, contributing to nearly 33%of the total worldwide deaths, with myocardial infarction (MI, heart attack) as a major attributor [1,2].The tissue damage associated with myocardial infraction has been ascribed to reactive oxygen species (ROS) and numerous related pathways such as tumor protein p53 (p53), AMP-activated proteinAntioxidants 2020, 9, 977; doi:10.3390/antiox9100977 www.mdpi.com/journal/antioxidantsAntioxidants 2020, 9, 977 kinase (AMPK) [3], mitogen-activated protein kinases (p38 kinase, c-Jun N-terminal kinases (JNK)and extracellular signal-regulated protein kinase (ERK1/2)) [1] and Kelch-like ECH-associated protein1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1). Nrf is an oxidation-reduction-sensitive transcription factor that binds to antioxidant response elements (AREs), promoting cell survival gene expression, inhibiting apoptosis, controlling mitochondrial function, and stimulating antioxidant enzyme expression and, moderating oxidative damage [4]. Under oxidative stress or in response to other damaging stimuli, Nrf escapes Keap1-mediated inhibition in the cytoplasm and accumulates in the nucleus, leading to the transcriptional launch of phase II enzymes/antioxidant genes, including HO-1, Glutathione-S-transferase (GST), glutamate-cysteine ligase, catalytic subunit (GCLC), etc. Within the complex autophagy signaling web, two established pathways have been extensively designated for autophagy regulation [7]; phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and AMPK. (Keap1), nuclear factor erythroid 2-related factor 2 (Nrf2), and other downstream antioxidant enzymes, as well as the expression of phosphoinositide 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and other downstream apoptotic and inflammatory mediators
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