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Gastrodin alleviates cardiac hypertrophy by inhibition of insulin-like growth factor type 2/insulin-like growth factor type 2 receptor

ABSTRACT: Background: Pathological cardiac hypertrophy is commonly associated with upregulation of fetal genes, fibrosis, cardiac dysfunction and leads to heart failure. Previous studies demonstrated that gastrodin (GAS) inhibited cardiac hypertrophy and thus improved cardiac function. However, the theraputic targets by which GAS regulates in the regression of cardiac hypertrophy has not been well elucidated yet. Methods: A mouse model of myocardial hypertrophy was estavlished by angiotensin II (Ang II) induction, then treated with GAS (0, 5 or 50 mg/kg/d) combined with the sham-operated controls. Heart samples from each dose group were collected for the next RNA sequencing.Through bioinformatics analysis, the key differentially expressed genes (DEG) involved in the recovery of cardiac function were identidied. They were further confirmed by quantitative real-time PCR (qRT-PCR) and western blotting in neonatal rat cardiomyocytes (NRCMs). Results: We identified 620 up-regulated and 87 down-regulated DEGs induced by Ang II, of which the expression patterns of 58 and 146 genes were reversed by low-dose and high-dose GAS, respectively. These reversed DEGs are mainly enriched in biological processs of regulation of Ras protein signal transduction, heart contraction, covalent chromatin modification, glucose metabolism and positive regulation of cell cycle. Among them, insulin-like growth factor type 2 (Igf2) gene, which was highly reversed and down-regulated by GAS, served as the core gene linking energy metabolism, immune regulation and system development. Subsequent functional verification demonstrated that the system of Igf2 and its receptor Igf2r is one of the targets of GAS in the treatment of cardiac hypertrophy, and knocking out Igf2r can protect NRCM from cardiac hypertrophy. Conclusions: Taken together, we, for the first time, identified Igf2/Igf2r as a therapeutic target influenced by GAS in the pharmacological intervention of cardiac hypertrophy

ORGANISM(S): Mus musculus

PROVIDER: GSE164187 | GEO | 2021/01/05

REPOSITORIES: GEO

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Project description:Background: Heart failure (HF), characterized by cardiac remodeling, is associated with abnormal epigenetic processes and aberrant gene expression. Here, we aimed to elucidate the effects and mechanisms of N-acetyltransferase 10 (NAT10)-mediated N4?acetylcytidine (ac4C) acetylation during cardiac remodeling. Methods: NAT10 and ac4C expression were detected in both human and mouse subjects with cardiac remodeling through multiple assays. Subsequently, acetylated RNA immunoprecipitation and sequencing (acRIP-seq), thiol (SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq), and ribosome sequencing (Ribo-seq) were employed to elucidate the role of ac4C-modified post-transcriptional regulation in cardiac remodeling. Additionally, functional experiments involving the overexpression or knockdown of NAT10 were conducted in mice models challenged with Ang II and transverse aortic constriction (TAC). Results: NAT10 expression and RNA ac4C levels were increased in in vitro and in vivo cardiac remodeling models, as well as in patients with cardiac hypertrophy. Silencing and inhibiting NAT10 attenuated Ang II-induced cardiomyocyte hypertrophy and cardio-fibroblast activation. Next-generation sequencing revealed ac4C changes in both mice and humans with cardiac hypertrophy were associated with changes in global mRNA abundance, stability and translation efficiency. Mechanistically, NAT10 could enhance the stability and translation efficiency of CD47 and ROCK2 transcripts by upregulating their mRNA ac4C modification, thereby resulting in an increase in their protein expression during cardiac remodeling. Furthermore, the administration of Remodelin, a NAT10 inhibitor, has been shown to prevent cardiac functional impairments in mice subjected to TAC by suppressing cardiac fibrosis, hypertrophy, and inflammatory responses, while also regulating the expression levels of CD47 and ROCK2. Conclusions: Therefore, our data suggest that modulating epitranscriptomic processes, such as ac4C acetylation through NAT10, may be a promising therapeutic target against cardiac remodeling.

Project description:Background: Vitamin D deficiency is associated with cardiac hypertrophy and heart failure, and vitamin D therapy prevents the progression of cardiac hypertrophy in animal models. Here, we examine whether vitamin D therapy regresses pre-existing cardiac hypertrophy, and prevents the progression to heart failure. Methods and Results: When male Dahl salt-sensitive (DSS) rats are fed a high salt (HS) diet, all rats develop cardiac hypertrophy after 5 weeks (H). Thereafter, rats were treated with vehicle (V), paricalcitol (PC, an active vitamin D analog at 200ng, IP 3x/wk), enalapril (EP, 90ug/day), and PC+EP. All groups were continued on the HS diet and evaluated after 4 weeks of therapy. The PC and PC+EP, but not the V and EP-only groups, showed significant regression of pre-existing cardiac hypertrophy. The signs of decompensated heart failure were evident in the vehicle-treated group; these heart failure parameters significantly improved with PC, EP or PC+EP therapy. The expression of PKCe, which is regulated by Ca2+ and known to stimulate cardiac hypertrophy, was significantly increased in the vehicle group, and PC, EP or PC+EP effectively decreased PKCe activation. We also observed normalization of genetic alterations during progression to heart failure with PC treatment. Conclusions: PC treatment resulted in both the regression of pre-existing cardiac hypertrophy, and the attenuation of the progression to heart failure, compared to improvement in progression to heart failure by EP alone. These beneficial findings in the heart were associated with inhibition of PKCe activation, and reversal of gene alterations. Male Dahl salt-sensitive rats (Harlan Sprague–Dawley, Somerville, NJ) were bred and fed a normal diet until 6 weeks of age. To generate pressure overload cardiac hypertrophy, they were then fed a high salt (6%NaCl) diet for the next 5 weeks. Data for baseline hypertrophic group (H) was obtained at the end of 11 weeks. Among H group animals, they were divided as follows and treated for an additional 4 weeks: 1) continuation of the HS diet with vehicle injection (H+V); 2) continuation of the HS diet with paricalcitol (19-nor-1,25-(OH)2 D2) (PC) (200ng IP 3x/wk) injection (H+PC); 3) continuation of the HS diet with low dose enalapril (EP), an angiotensin-converting enzyme inhibitor, infusion via osmotic pump and vehicle injection (H+EP+V); and 4) continuation of the HS diet with low dose EP infusion via osmotic pump and PC (200ng IP 3x/wk) injection (H+EP+PC). PC was prepared with 95% propylene glycol and 5% ethyl alcohol solution and administered three times a week on Monday, Wednesday, and Friday for 4 consecutive weeks. Vehicle groups received vehicle injections on the same schedule. Two groups of rats were implanted with pumps to deliver EP for 4 weeks. Since the reduction in blood pressure (BP) from high doses of EP would have effects on cardiac hypertrophy and progression to heart failure, we used low dose EP at 90ug/day, a maximum dose that did not significantly decrease BP in these rats, to study the effects of EP and PC that are independent of BP.

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Gastrodin alleviates cardiac hypertrophy by inhibition of insulin-like growth factor type 2/insulin-like growth factor type 2 receptor

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