Fibroblast growth factor 21 protects the heart from angiotensin II-induced cardiac hypertrophy and dysfunction via SIRT1.
This study investigated the mechanism through which fibroblast growth factor 21 (FGF21) protects against angiotensin II (Ang II)-induced cardiac hypertrophy and dysfunction.
Male silent information regulator 1 (SIRT1) flox/flox and cardiomyocyte-specific inducible SIRT1 knockout mice (SIRT1-iKO) were generated and treated with Ang II (1.1 mg/kg/day for 4 weeks) at the age of 8-12-week-old. FGF21 treatment [2.5 mg/kg/day for 4 weeks by intraperitoneal (i.p.) injection] was initiated at the same time as the Ang II infusion. For in vitro studies, neonatal rat cardiomyocytes (NRCMs), H9c2 rat cardiomyocytes and isolated adult mouse cardiomyocytes were treated with Ang II (1 μM) and FGF21 (20 nM) for 24 h with or without SIRT1 silencing.
FGF21 treatment significantly attenuated Ang II-induced cardiac hypertrophy and dysfunction. SIRT1 knockout abolished the ability of FGF21 to prevent Ang II-induced cardiac hypertrophy, fibrosis, and apoptosis, without affecting the beneficial effects of FGF21 in Ang II-induced hypertension, and did not influence the hypertension itself. FGF21 markedly increased the deacetylase activity of SIRT1 and promoted the interaction of SIRT1 with liver kinase B1 (LKB1) and forkhead box protein O1 (FoxO1), resulting in decreased acetylation of these SIRT1 target proteins. Consequently, FGF21 promoted the activation of the LKB1 target adenosine monophosphate-activated protein kinase (AMPK) and altered the transcriptional activity of FoxO1 on its downstream target genes catalase (Cat), MnSOD (Sod2), and Bim, resulting in reduced reactive oxygen species (ROS) accumulation and cardiomyocyte apoptosis.
FGF21 improves cardiac function and alleviates Ang II-induced cardiac hypertrophy in a SIRT1-dependent manner.
Li S
,Zhu Z
,Xue M
,Yi X
,Liang J
,Niu C
,Chen G
,Shen Y
,Zhang H
,Zheng J
,Zhao C
,Liang Y
,Cong W
,Wang Y
,Jin L
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Glycyrrhiza glabra (Licorice) root extract attenuates doxorubicin-induced cardiotoxicity via alleviating oxidative stress and stabilising the cardiac health in H9c2 cardiomyocytes.
Doxorubicin (DOX) is an effective anti-neoplastic drug, however; it has downside effects on cardiac health and other vital organs. The herbal remedies used in day to day life may have a beneficial effect without disturbing the health of the vital organs. Glycyrrhiza glabra L. is a ligneous perennial shrub belonging to Leguminosae/Fabaceae/Papilionaceae family growing in Mediterranean region and Asia and widespread in Turkey, Italy, Spain, Russia, Syria, Iran, China, India and Israel. Commonly known as mulaithi in north India, G. glabra has glycyrrhizin, glycyrrhetic acid, isoliquiritin, isoflavones, etc., which have been reported for several pharmacological activities such as anti-demulcent, anti-ulcer, anti-cancer, anti-inflammatory and anti-diabetic.
The objective of the present study is to investigate the interaction between the molecular factors like PPAR-α/γ and SIRT-1 during cardiac failure arbitrated by DOX under in vitro conditions and role of Glycyrrhiza glabra (Gg) root extract in alleviating these affects.
In the present study, we have examined the DOX induced responses in H9c2 cardiomyocytes and investigated the role of phytochemical Glycyrrhiza glabra in modulating these affects. MTT assay was done to evaluate the cell viability, Reactive Oxygen Species (ROS)/Reactive Nitrogen Species (RNS) levels, mitochondrial ROS, mitochondrial membrane potential was estimated using fluorescent probes. The oxidative stress in terms of protein carbonylation, lipid peroxidation and DNA damage was detected via spectrophotometric methods and immune-fluorescence imaging. The cardiac markers and interaction between SIRT-1 and PPAR-α/γ was measured using Real-Time PCR, Western blotting and Co-immunoprecipitation based studies.
The Glycyrrhiza glabra (Gg) extracts maintained the membrane integrity and improved the lipid homeostasis and stabilized cytoskeletal element actin. Gg phytoextracts attenuated aggravated ROS level, repaired the antioxidant status and consequently, assisted in repairing the DNA damage and mitochondrial function. Further, the expression of hypertrophic markers in the DOX treated cardiomyocytes reconciled the expression factors both at the transcriptional and translational levels after Gg treatment. SIRT-1 mediated pathway and its downstream activator PPARs are significant in maintaining the cellular functions. It was observed that the Gg extract allows regaining the nuclear SIRT-1 and PPAR-γ level which was otherwise reduced with DOX treatment in H9c2 cardiomyocytes. The co-immunoprecipitation (Co-IP) documented that SIRT-1 interacts with PPAR-α in the untreated control H9c2 cardiomyocytes whereas DOX treatment interferes and diminishes this interaction however the Gg treatment maintains this interaction. Knocking down SIRT-1 also downregulated expression of PPAR-α and PPAR-γ in DOX treated cells and Gg treatment was able to enhance the expression of PPAR-α and PPAR-γ in SIRT-1 knocked down cardiomyocytes.
The antioxidant property of Gg defend the cardiac cells against the DOX induced toxicity via; 1) reducing the oxidative stress, 2) maintaining the mitochondrial functions, 3) regulating lipid homeostasis and cardiac metabolism through SIRT-1 pathway, and 4) conserving the cardiac hypertrophy and hence preserving the cardiomyocytes health. Therefore, Gg can be recommended as a healthy supplement with DOX towards cancer therapeutics associated cardiotoxicity.
Upadhyay S
,Mantha AK
,Dhiman M
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