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IFI-16 inhibition attenuates myocardial remodeling following myocardial infarction.

ABSTRACT: Myocardial remodeling (MR) following myocardial infarction (MI) contributes to heart failure. Inflammation is a key determinant in cardiac remodeling, with potential prognostic improvements by inhibiting inflammatory factors. Pattern recognition receptors, including interferon gamma-inducible protein-16 (IFI-16), play significant roles in this process, yet its specific involvement remains underexplored. This study investigates IFI-16's role in initiating inflammation via the inflammasome and its direct interaction with galectin-3 protein post-MI. Elevated IFI-16 levels were observed in human and rat myocytes and a mouse MI model under hypoxic, nutrient-deprived conditions, correlating with increased inflammation-associated proteins. Suppression of IFI-16/IFI-204 using short hairpin RNA (shRNA) lentivirus or adeno-associated virus decreased inflammatory factor activation, thereby mitigating remodeling and enhancing cardiac function post-MI. Co-immunoprecipitation (coIP) and double-fluorescence staining confirmed IFI-16's ability to interact directly with galectin-3. These findings underscore IFI-16's critical role as a pro-inflammatory factor in post-MI MR, suggesting its inhibition as a potential therapeutic strategy.

SUBMITTER: Deng Y

PROVIDER: S-EPMC11345598 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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IFI-16 inhibition attenuates myocardial remodeling following myocardial infarction.

Deng Yi Y Pang Xiuqing X Chen Li L Peng Weihang W Huang Xiaoyan X Huang Peiying P Zhao Shuai S Li Zhishang Z Cai Xingui X Huang Qiuping Q Zeng Jing J Feng Yuchao Y Chen Bojun B

iScience 20240723 8

Myocardial remodeling (MR) following myocardial infarction (MI) contributes to heart failure. Inflammation is a key determinant in cardiac remodeling, with potential prognostic improvements by inhibiting inflammatory factors. Pattern recognition receptors, including interferon gamma-inducible protein-16 (IFI-16), play significant roles in this process, yet its specific involvement remains underexplored. This study investigates IFI-16's role in initiating inflammation via the inflammasome and its ...[more]

PMID: 39188985

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Project description:PurposeNitric oxide (NO) is constitutively produced and released from the endothelium and several blood cell types by the isoform 3 of the NO synthase (NOS3). We have shown that NO protects against myocardial ischemia/reperfusion (I/R) injury and that depletion of circulating NOS3 increases within 24 h of ischemia/reperfusion the size of myocardial infarction (MI) in chimeric mice devoid of circulating NOS3. In the current study we hypothesized that circulating NOS3 also affects remodeling of the left ventricle following reperfused MI.MethodsTo analyze the role of circulating NOS3 we transplanted bone marrow of NOS3-/- and wild type (WT) mice into WT mice, producing chimerae expressing NOS3 only in vascular endothelium (BC-/EC+) or in both, blood cells and vascular endothelium (BC+/EC+). Both groups underwent 60 min of coronary occlusion in a closed-chest model of reperfused MI. During the 3 weeks post MI, structural and functional LV remodeling was serially assessed (24 h, 4 d, 1 w, 2 w and 3 w) by echocardiography. At 72 hours post MI, gene expression of several extracellular matrix (ECM) modifying molecules was determined by quantitative RT-PCR analysis. At 3 weeks post MI, hemodynamics were obtained by pressure catheter, scar size and collagen content were quantified post mortem by Gomori's One-step trichrome staining.ResultsThree weeks post MI, LV end-systolic (53.2±5.9 μl; ***p≤0.001; n = 5) and end-diastolic volumes (82.7±5.6 μl; *p<0.05; n = 5) were significantly increased in BC-/EC+, along with decreased LV developed pressure (67.5±1.8 mm Hg; n = 18; ***p≤0.001) and increased scar size/left ventricle (19.5±1.5%; n = 13; **p≤0.01) compared to BC+/EC+ (ESV: 35.6±2.2 μl; EDV: 69.1±2.6 μl n = 8; LVDP: 83.2±3.2 mm Hg; n = 24; scar size/LV13.8±0.7%; n = 16). Myocardial scar of BC-/EC+ was characterized by increased total collagen content (20.2±0.8%; n = 13; ***p≤0.001) compared to BC+/EC+ (15.9±0.5; n = 16), and increased collagen type I and III subtypes.ConclusionCirculating NOS3 ameliorates maladaptive left ventricular remodeling following reperfused myocardial infarction.

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IFI-16 inhibition attenuates myocardial remodeling following myocardial infarction.

Publications

IFI-16 inhibition attenuates myocardial remodeling following myocardial infarction.

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