Zhaohui Pei1, Yandong Liu2, Suqin Liu3, Wei Jin2, Yuanfei Luo2, Mingming Sun4, Yu Duan5, Amir Ajoolabady6, James R Sowers7, Yan Fang8, Feng Cao8, Haixia Xu9, Yaguang Bi10, Shuyi Wang11, Jun Ren12. 1. The Second Department of Cardiology, The Third Hospital of Nanchang, Nanchang 200072, China. Electronic address: peizhaohui@email.ncu.edu.cn. 2. The Second Department of Cardiology, The Third Hospital of Nanchang, Nanchang 200072, China. 3. The Second Department of Cardiology, The Third Hospital of Nanchang, Nanchang 200072, China; Nanchang University, Nanchang, Jiangxi 330006, China. 4. University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China. 5. Department of Cardiology, Xijing Hospital, the Air Force Military Medical University, Xi'an 710032, China. 6. University of Wyoming College of Health Sciences, Laramie, WY 82071, USA. 7. Diabetes and Cardiovascular Research Center, University of Missouri Columbia, Columbia, MO 65212, USA. 8. Department of Cardiology, the Second Medical Center of the China PLA General Hospital, Beijing 100853, China. 9. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Cardiology, Affiliated Hospital of Nantong University, Jiangsu 226001, China. 10. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China. 11. University of Wyoming College of Health Sciences, Laramie, WY 82071, USA; Shanghai University School of Medicine, Shanghai 200044, China. Electronic address: shuyiwang23@outlook.com. 12. Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA. Electronic address: jren@uw.edu.
Abstract
OBJECTIVE: Ferroptosis is indicated in cardiovascular diseases. Given the prominent role of mitophagy in the governance of ferroptosis and our recent finding for FUN14 domain containing 1 (FUNDC1) in obesity anomalies, this study evaluated the impact of FUNDC1 deficiency in high fat diet (HFD)-induced cardiac anomalies. METHODS AND MATERIALS: WT and FUNDC1-/- mice were fed HFD (45% calorie from fat) or low fat diet (LFD, 10% calorie from fat) for 10 weeks in the presence of the ferroptosis inhibitor liproxstatin-1 (LIP-1, 10 mg/kg, i.p.). RESULTS: RNAseq analysis for differentially expressed genes (DEGs) reported gene ontology term related to ferroptosis and mitophagy in obese rat hearts, which was validated in obese rodent and human hearts. Although 10-week HFD intake did not alter global metabolism, cardiac geometry and function, ablation of FUNDC1 unmasked metabolic derangement, pronounced cardiac remodeling, contractile, intracellular Ca2+ and mitochondrial anomalies upon HFD challenge, the effects of which with exception of global metabolism were attenuated or mitigated by LIP-1. FUNDC1 ablation unmasked HFD-evoked rises in fatty acid synthase ACSL4, necroptosis, inflammation, ferroptosis, mitochondrial O2- production, and mitochondrial injury as well as dampened autophagy and DNA repair enzyme 8-oxoG DNA glycosylase 1 (OGG1) but not apoptosis, the effect of which except ACSL4 and its regulator SP1 was reversed by LIP-1. In vitro data noted that arachidonic acid, an ACSL4 substrate, provoked cytochrome C release, cardiomyocyte defect, and lipid peroxidation under FUNDC1 deficiency, the effects were interrupted by inhibitors of SP1, ACSL4 and ferroptosis. CONCLUSIONS: These data suggest that FUNDC1 deficiency sensitized cardiac remodeling and dysfunction with short-term HFD exposure, likely through ACSL4-mediated regulation of ferroptosis.
OBJECTIVE: Ferroptosis is indicated in cardiovascular diseases. Given the prominent role of mitophagy in the governance of ferroptosis and our recent finding for FUN14 domain containing 1 (FUNDC1) in obesity anomalies, this study evaluated the impact of FUNDC1 deficiency in high fat diet (HFD)-induced cardiac anomalies. METHODS AND MATERIALS: WT and FUNDC1-/- mice were fed HFD (45% calorie from fat) or low fat diet (LFD, 10% calorie from fat) for 10 weeks in the presence of the ferroptosis inhibitor liproxstatin-1 (LIP-1, 10 mg/kg, i.p.). RESULTS: RNAseq analysis for differentially expressed genes (DEGs) reported gene ontology term related to ferroptosis and mitophagy in obeserat hearts, which was validated in obese rodent and human hearts. Although 10-week HFD intake did not alter global metabolism, cardiac geometry and function, ablation of FUNDC1 unmasked metabolic derangement, pronounced cardiac remodeling, contractile, intracellular Ca2+ and mitochondrial anomalies upon HFD challenge, the effects of which with exception of global metabolism were attenuated or mitigated by LIP-1. FUNDC1 ablation unmasked HFD-evoked rises in fatty acid synthase ACSL4, necroptosis, inflammation, ferroptosis, mitochondrial O2- production, and mitochondrial injury as well as dampened autophagy and DNA repair enzyme 8-oxoG DNA glycosylase 1 (OGG1) but not apoptosis, the effect of which except ACSL4 and its regulator SP1 was reversed by LIP-1. In vitro data noted that arachidonic acid, an ACSL4 substrate, provoked cytochrome C release, cardiomyocyte defect, and lipid peroxidation under FUNDC1 deficiency, the effects were interrupted by inhibitors of SP1, ACSL4 and ferroptosis. CONCLUSIONS: These data suggest that FUNDC1deficiency sensitized cardiac remodeling and dysfunction with short-term HFD exposure, likely through ACSL4-mediated regulation of ferroptosis.
Authors: Amir Ajoolabady; Simin Liu; Daniel J Klionsky; Gregory Y H Lip; Jaakko Tuomilehto; Sina Kavalakatt; David M Pereira; Afshin Samali; Jun Ren Journal: Trends Pharmacol Sci Date: 2021-12-08 Impact factor: 14.819