The protective effect of kaempferol on heart via the regulation of Nrf2, NF‐κβ, and PI3K/Akt/GSK‐3β signaling pathways in isoproterenol‐induced heart failure in diabetic rats

Abstract

This study was designed to delineate the effect of kaempferol (KF) on heart failure (HF) in diabetic rats. Streptozotocin‐induced male diabetic rats received KF orally at 10 and 20 mg/kg for 42 consecutive days. In last 2 days of the experimental period, isoproterenol was subcutaneously injected at 85 mg/kg to induce HF. The hearts were processed for hemodynamic, biochemical, molecular, and histological investigations. Systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure were elevated in KF‐treated HF‐induced diabetic rats. Moreover, KF treatment resulted in decreased fasting blood glucose and glycosylated hemoglobin levels with increased serum insulin levels. Besides, serum cardiac injury markers like troponin‐I, creatine kinase‐muscle/brain, lactate dehydrogenase, and brain natriuretic peptide levels were significantly reduced in KF treatment. KF treatment has shown decrease in cardiac heme oxygenase‐1, nuclear factor erythroid 2–related factor 2 (Nrf‐2), and γ‐glutamylcysteine synthetase with increased Keap1 mRNA levels. The cardioprotection of KF was improved by inhibition of apoptosis via blocking phosphorylation of Akt/glycogen synthase kinase (GSK)‐3β and p38 mitogen‐activated protein‐kinase/extracellular signal‐regulated kinases signaling pathways in HF‐induced diabetic rats. Moreover, reduced cardiac apoptosis in KF treatment was confirmed by decreased terminal deoxynucleotidyl transferase dUTP nick‐end labeling (TUNEL) positive cells, histopathological changes in HF‐induced diabetic rats. Therefore, the cardioprotective effect of KF is attributed to the regulation of Nrf2, nuclear factor kappa‐light‐chain‐enhancer of activated B cells, and Akt/GSK‐3β signaling pathways in HF‐induced diabetic rats.

Kaempferol suppresses acetaminophen-induced liver damage by upregulation/activation of SIRT1

“…and prevents the formation of hydroxyl radicals (OH -) by chelating several ions like ferrous and cuprous (Van Acker et al 1996;Mira et al 2002). Furthermore, kaempferol increases the expression of several antioxidant enzymes and GSH by upregulating their master regulator including nuclear Nrf-2, and the heme oxygenase-1 gene (Maridonneau-Parini 1986;Ozgova et al 2003;Doronicheva et al 2007;Hong et al 2009;Calder on-Montaño et al 2011;Zhang et al 2019). Therefore, it is possible that kaempferol improved MnSOD and GSH in the livers of the control and APAP-treated rats by upregulation/activation of the Nrf-2/HO-1 axis.…”

Exploring Molecular Mechanism of Huangqi in Treating Heart Failure Using Network Pharmacology

“…Study shows that calycosin and formononetin inhibit the activation of the renin-angiotensin-aldosterone system to improve the symptoms of HF [29]. Kaempferol plays a cardioprotective role by inhibiting Nrf2, NF-κB, and Akt/GSK-3β signaling pathways to reduce apoptosis [30]. Hederagenin reduces the cascade of inflammatory responses by inhibiting IKKβ/NF-κB signaling pathway to improve coronary hemorheology and regulate endothelial dysplasia [31].…”

Kaempferol Protects Blood Vessels From Damage Induced by Oxidative Stress and Inflammation in Association With the Nrf2/HO-1 Signaling Pathway

“…Of these, kaempferol (Kae) is well known for its pharmacological ability to reduce oxidative stress and inflammation in various organs and tissues ( Kampkotter et al., 2007 ; Park et al., 2009 ; Ren et al., 2019 ). Recent studies have demonstrated the protective effects of Kae on the heart by regulating nuclear factor erythroid-2 related factor (Nrf2) and nuclear factor kappa B (NF-κB) ( Suchal et al., 2016 ; Chen et al., 2018 ; Zhang et al., 2019 ). Of these factors, Nrf2, a master transcription factor, is transferred to the nucleus after activation, where it binds to the upstream cis-regulated antioxidant response element (ARE) sequence located in the promoter regions of genes responsible for cell protection ( David et al., 2017 ).…”