Protective Effect of Geraniol on Oxidative, Inflammatory and Apoptotic Alterations in Isoproterenol-Induced Cardiotoxicity: Role of the Keap1/Nrf2/HO-1 and PI3K/Akt/mTOR Pathways

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).

Role of PI3K in the Progression and Regression of Atherosclerosis

“…For example, geraniol and levosimendan regulate autophagy to reduce oxidative stress and limit the inflammation cascade through PI3K/Akt/mTOR. Because levosimendan can inhibit aggregation, it is more suitable for hypercoagulation and hyperlipidemia ( Tawfik et al, 2018 ; Younis et al, 2020 ).…”

7β-(3-Ethyl-cis-crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro-Z Notonipetranone Attenuates Neuropathic Pain by Suppressing Oxidative Stress, Inflammatory and Pro-Apoptotic Protein Expressions

“…Oxidative stress leads to the activation of reactive oxygen species which as a result amplifies the pathogenesis of neuropathic pain [ 21 , 22 , 23 ]. It has been reported that the underlying cause of oxidative stress-mediated neuropathic pain is the under-expression of Nrf2 [ 24 , 25 , 26 ], a transcription factor involved in the regulation of genes that encodes antioxidant proteins and phase 2 detoxifying enzymes [ 27 , 28 , 29 ]. Nrf2 binding with the antioxidant responsive element (ARE) leads to the transcriptional activation of downstream genes such as NAD(P)H: quinone oxidoreductase (NQO1), glutathione-S-transferase (GST), and hemeoxygenase-1 (HO-1) [ 27 , 30 , 31 , 32 ].…”

Keap1/Nrf2 Signaling Pathway

“…Therefore, investigations of the protective effects of Keap1/Nrf2 signaling that focus on specific tissues or organs are of great interest. Such studies have traditionally focused on tissues with detoxification functions such as the liver [ 6 , 7 ] but have also expanded to diverse tissues, including the kidney [ 8 , 9 ], skin [ 10 ], lung [ 11 ], colon [ 12 ], heart [ 13 ], nervous system [ 14 ], adipose tissue [ 15 ], pancreas [ 16 ] and thyroid [ 17 , 18 ], as evidenced by the respective tissue/organ-specific studies that are outlined below and comprise the majority of studies in the present Special Issue. Lastly, research on Nrf2 has expanded to encompass not only basic but also translational and clinical studies.…”

“…Reactive oxygen species are produced by mitochondria during activity in various muscle tissues, including the heart, where the role of Keap1/Nrf2 signaling in ischemia–reperfusion injury has been well established [ 32 ]. In a study using rats, Younis et al extend these observations by showing that geraniol, an Nrf2-activating phytochemical, has protective effects on oxidative, inflammatory and apoptotic alterations in isoproterenol-induced myocardial infarction [ 13 ]. Similar to the aforementioned studies, involvement of Keap1/Nrf2 signaling is inferred indirectly by the induction of antioxidant and cytoprotective genes.…”