Key result
SIRT3 ablation worsens cardiac dysfunction and fibrosis in high-fat diet mice via ROS-NF-κB-MCP-1 signaling.
Why the study?
Although obesity promotes cardiac remodeling characterized by inflammation and fibrosis, the role of the main mitochondrial deacetylase SIRT3 in this process remains unclear.
Does SIRT3 ablation exacerbate obesity-related cardiac remodeling in mice fed a high-fat diet?
Does SIRT3 ablation exacerbate obesity-related cardiac remodeling in mice fed a high-fat diet?
SIRT3 prevents obesity-related cardiac remodeling by attenuating cardiac inflammation and fibrosis through modulation of the ROS-NF-κB-MCP-1 pathway.
Highlights SIRT3's protective role in obese mice; leaves open clinical translation and therapeutic targeting.
Obesity and the associated complications are a major public health issue as obesity incidence increases yearly, worldwide. Effects of obesity on heart failure have been reported previously. Obesity-related cardiac remodeling includes structural and functional dysfunctions, in which cardiac inflammation and fibrosis play a key role. The main mitochondrial deacetylase, SIRT3 participates in numerous cellular processes; however, its role in obesity-related cardiac remodeling remains unclear. In our study, high-fat diet (HFD) feeding induced downregulation of SIRT3 protein level in mice. SIRT3-KO mice fed on HFD exhibited higher cardiac dysfunction and cardiac remodeling compared with the wild-type controls. Further study revealed increases in collagen accumulation and inflammatory cytokine expression including MCP-1, IL-6, TGF-β, TNF-α in mice fed on HFD compared with chow diet, with higher levels observed in SIRT3-KO mice. Furthermore, significantly high levels of cardiac MCP-1 expression and macrophage infiltration, and ROS generation and activated NF-κB were observed in HFD-fed SIRT3-KO mice. We presumed that SIRT3 ablation-mediated MCP-1 upregulation is attributed to ROS-NF-κB activation. Thus, we concluded that SIRT3 prevents obesity-related cardiac remodeling by attenuating cardiac inflammation and fibrosis, through modulation of ROS-NF-κB-MCP-1 pathway.
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Guo et al. (2020) studied Obesity-related cardiac remodeling. SIRT3 ablation (SIRT3-KO) and high-fat diet vs. Wild-type controls and chow diet was evaluated on Cardiac dysfunction and cardiac remodeling. SIRT3 ablation in mice fed a high-fat diet exacerbated cardiac dysfunction, inflammation, and fibrosis via the ROS-NF-κB-MCP-1 signaling pathway.
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