General Information of the Disease (ID: DIS00097)
Name
Congestive heart failure
ICD
ICD-11: BD10
Full List of Target(s) of This Ferroptosis-centered Disease
Prostaglandin G/H synthase 2 (PTGS2)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Marker
Responsed Disease Heart failure [ICD-11: BD10]
Responsed Drug Atorvastatin Investigative
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
8-week C57BL/6J male mice purchased from Comparative Medicine Center of Yangzhou University were retained with unrestricted access to sterilized diet and water at standard bio-clean laboratory settings (Experimental Animal Center of College of Veterinary Medicine of Yangzhou University). Animals were randomly divided into four groups(n = 6-8 mice per group): control group or ISO group: injected with saline or ISO (5 mg/kg) subcutaneously for 14 days and, meanwhile, received vehicle saline via gavage for 14 days respectively; ATV (Pfizer,USA) group or ISO + ATV group: injected with saline or 5 mg/kg ISO (Sigma, USA) subcutaneously for 14 days and, meanwhile, received 20 mg/kg ATV via gavage for 14 days respectively.

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Response regulation Atorvastatin showed significantly protective effects through suppressing the activation of ferroptosis related signaling, as evidenced by decreasing the mRNA levels of PTGS2 (a marker of ferroptosis), contents of malonaldehyde and protein levels of NOX4 and increasing the contents of glutathione (GSH), the ratio of GSH/GSSG and protein levels of GPX4 and SLC7A11. ATV reduced cardiac hypertrophy and fibrosis and accumulation of iron in heart failure.
NADPH oxidase 4 (NOX4)
In total 3 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [2]
Target for Ferroptosis Driver
Responsed Disease Heart failure [ICD-11: BD10]
Responsed Drug Puerarin Phase 2
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
Male Sprague Dawley ratsweighing 80-100 g were used to make the HF model induced by descending aortic banding (AB) procedure. Rats receiving a similar procedure except for the arterial ligation were defined as the sham-operated (SO) group. After the procedure, echocardiography was immediately applied to confirm the arterial banding. Rats receiving subcutaneous injections of low- or high-dose puerarin (100 mg/kg/day and 200 mg/kg/day, respectively) after the AB procedure were respectively defined as the Pue1 and Pue2 groups. An equal volume of normal saline was injected into the rats of the SO and AB groups.

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Response regulation Ferroptosis is involved in the loss of myocytes during heart failure. Puerarin exerted protective effects against heart failure through inhibition of ferroptosis. And puerarin exerted protective effects against heart failure through inhibition of ferroptosis. Regulation of Nox4 signaling might be involved in puerarin inhibiting ferroptosis.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Driver
Responsed Disease Heart failure [ICD-11: BD10]
Responsed Drug Atorvastatin Investigative
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
8-week C57BL/6J male mice purchased from Comparative Medicine Center of Yangzhou University were retained with unrestricted access to sterilized diet and water at standard bio-clean laboratory settings (Experimental Animal Center of College of Veterinary Medicine of Yangzhou University). Animals were randomly divided into four groups(n = 6-8 mice per group): control group or ISO group: injected with saline or ISO (5 mg/kg) subcutaneously for 14 days and, meanwhile, received vehicle saline via gavage for 14 days respectively; ATV (Pfizer,USA) group or ISO + ATV group: injected with saline or 5 mg/kg ISO (Sigma, USA) subcutaneously for 14 days and, meanwhile, received 20 mg/kg ATV via gavage for 14 days respectively.

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Response regulation Atorvastatin showed significantly protective effects through suppressing the activation of ferroptosis related signaling, as evidenced by decreasing the mRNA levels of PTGS2 (a marker of ferroptosis), contents of malonaldehyde and protein levels of NOX4 and increasing the contents of glutathione (GSH), the ratio of GSH/GSSG and protein levels of GPX4 and SLC7A11. ATV reduced cardiac hypertrophy and fibrosis and accumulation of iron in heart failure.
Experiment 3 Reporting the Ferroptosis-centered Disease Response by This Target [3]
Target for Ferroptosis Driver
Responsed Disease Heart failure [ICD-11: BD10]
Responsed Regulator Toll-like receptor 4 (TLR4) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Autophagy hsa04140
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model rHTs (Rat hippocampal tissues)
In Vivo Model
Present animal studies used male Sprague Dawley rats (80-100 g) to create a HF model induced by the descending aortic banding (AB) procedure. The sham-operated (SO) group was defined as rats subjected to a similar procedure with the exception of arterial ligation. Echocardiography was applied to confirm the arterial banding immediately after the surgical procedure.

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Response regulation TLR4 or NOX4 knock-down significantly improved left ventricular remodeling and reduced myocytes death. Simultaneously, activated autophagy and ferroptosis in rats with heart failure (HF) were remarkably retarded by either TLR4 and NOX4 knock-down, suggesting TLR4-NOX4 as a potential therapeutic target for HF through inhibiting autophagy- and ferroptosis-mediated cell death.
Ferritin heavy chain (FTH1)
In total 2 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [4]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Heart failure [ICD-11: BD10]
Responsed Regulator hsa-miR-224-5p (miRNA) Driver
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model mMTs (Mouse myocardial tissues)
In Vivo Model
Six-week-old male C57/BL6J mice (weighting ~18-20 g) were supplied by the Shenyang Military Region General Hospital Experimental Animal Center. The mice were fed a standard diet and had unlimited access to drinking water. After 2 weeks of feeding, the mice were randomly assigned to TAC group (n = 15) and SHAM group (n = 16), and then anesthetized by intraperitoneal injection of 50 mg/kg pentobarbital sodium. To allow direct access to the transverse aorta, the mice a horizontal incision (5 mm in length) was made at the suprasternal notch. TAC operation was then performed by ligating the aorta between the right innominate and left carotid arteries using a 27G needle tied with 7-0 silk suture. The needle was promptly withdrawn, leaving the aortic constriction in place. The surgical procedure of mice in SHAM group was similar to that of mice in TAC group, except that the 7-0 silk suture was only crossed through the aortic arch without ligation.

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Response regulation MiR-224-5p was indeed the downstream target of circSnx12, and miR-224-5p could bind to the 3'-UTR region of FTH1 and regulate its expression level. Therefore, it is speculated that low circSnx12 expression and high miR-224-5p expression can downregulate FTH1 expression, directly regulate iron overload in myocardial cells, and ultimately leads to cardiac cell death. This new approach reveals potential circRNA targets for the treatment of heart failure.
Experiment 2 Reporting the Ferroptosis-centered Disease Response by This Target [4]
Target for Ferroptosis Marker/Suppressor
Responsed Disease Heart failure [ICD-11: BD10]
Responsed Regulator CircSnx12 (circRNA) Suppressor
Pathway Response Fatty acid metabolism hsa01212
Ferroptosis hsa04216
Cell Process Cell ferroptosis
In Vitro Model mMTs (Mouse myocardial tissues)
In Vivo Model
Six-week-old male C57/BL6J mice (weighting ~18-20 g) were supplied by the Shenyang Military Region General Hospital Experimental Animal Center. The mice were fed a standard diet and had unlimited access to drinking water. After 2 weeks of feeding, the mice were randomly assigned to TAC group (n = 15) and SHAM group (n = 16), and then anesthetized by intraperitoneal injection of 50 mg/kg pentobarbital sodium. To allow direct access to the transverse aorta, the mice a horizontal incision (5 mm in length) was made at the suprasternal notch. TAC operation was then performed by ligating the aorta between the right innominate and left carotid arteries using a 27G needle tied with 7-0 silk suture. The needle was promptly withdrawn, leaving the aortic constriction in place. The surgical procedure of mice in SHAM group was similar to that of mice in TAC group, except that the 7-0 silk suture was only crossed through the aortic arch without ligation.

    Click to Show/Hide
Response regulation MiR-224-5p was indeed the downstream target of circSnx12, and miR-224-5p could bind to the 3'-UTR region of FTH1 and regulate its expression level. Therefore, it is speculated that low circSnx12 expression and high miR-224-5p expression can downregulate FTH1 expression, directly regulate iron overload in myocardial cells, and ultimately leads to cardiac cell death. This new approach reveals potential circRNA targets for the treatment of heart failure.
Cystine/glutamate transporter (SLC7A11)
In total 1 item(s) under this target
Experiment 1 Reporting the Ferroptosis-centered Disease Response by This Target [1]
Target for Ferroptosis Suppressor
Responsed Disease Heart failure [ICD-11: BD10]
Responsed Drug Atorvastatin Investigative
Pathway Response Ferroptosis hsa04216
Fatty acid metabolism hsa01212
Cell Process Cell ferroptosis
Cell autophagy
In Vitro Model CHO-S/H9C2 cells Normal Cricetulus griseus CVCL_A0TS
In Vivo Model
8-week C57BL/6J male mice purchased from Comparative Medicine Center of Yangzhou University were retained with unrestricted access to sterilized diet and water at standard bio-clean laboratory settings (Experimental Animal Center of College of Veterinary Medicine of Yangzhou University). Animals were randomly divided into four groups(n = 6-8 mice per group): control group or ISO group: injected with saline or ISO (5 mg/kg) subcutaneously for 14 days and, meanwhile, received vehicle saline via gavage for 14 days respectively; ATV (Pfizer,USA) group or ISO + ATV group: injected with saline or 5 mg/kg ISO (Sigma, USA) subcutaneously for 14 days and, meanwhile, received 20 mg/kg ATV via gavage for 14 days respectively.

    Click to Show/Hide
Response regulation Atorvastatin showed significantly protective effects through suppressing the activation of ferroptosis related signaling, as evidenced by decreasing the mRNA levels of PTGS2 (a marker of ferroptosis), contents of malonaldehyde and protein levels of NOX4 and increasing the contents of glutathione (GSH), the ratio of GSH/GSSG and protein levels of GPX4 and SLC7A11. ATV reduced cardiac hypertrophy and fibrosis and accumulation of iron in heart failure.
References
Ref 1 Atorvastatin treatment ameliorates cardiac function and remodeling induced by isoproterenol attack through mitigation of ferroptosis. Biochem Biophys Res Commun. 2021 Oct 15;574:39-47. doi: 10.1016/j.bbrc.2021.08.017. Epub 2021 Aug 12.
Ref 2 Puerarin protects against heart failure induced by pressure overload through mitigation of ferroptosis. Biochem Biophys Res Commun. 2018 Feb 26;497(1):233-240. doi: 10.1016/j.bbrc.2018.02.061. Epub 2018 Feb 8.
Ref 3 Role of TLR4/NADPH oxidase 4 pathway in promoting cell death through autophagy and ferroptosis during heart failure. Biochem Biophys Res Commun. 2019 Aug 13;516(1):37-43. doi: 10.1016/j.bbrc.2019.06.015. Epub 2019 Jun 10.
Ref 4 circSnx12 Is Involved in Ferroptosis During Heart Failure by Targeting miR-224-5p. Front Cardiovasc Med. 2021 Apr 21;8:656093. doi: 10.3389/fcvm.2021.656093. eCollection 2021.