CTRP12 Ameliorated Lipopolysaccharide-Induced Cardiomyocyte Injury

Abstract

C1q/tumor necrosis factor (TNF)-related protein 12 (CTRP12) is a secretory protein that participates in the regulation of glucose and lipid metabolism in obesity and diabetes. Its role in cardiovascular disease, particularly sepsis-induced cardiac injury, is unclear. Here, we stimulated cardiomyocytes with lipopolysaccharide (LPS) to establish an in vitro cardiomyocyte injury model and CTRP12 was overexpressed with an adenovirus delivery system. Overexpression of CTRP12 reduced the transcription and release of pro-inflammatory cytokines from LPS-stimulated cardiomyocytes, including TNFα, interleukin-1 (IL-1), and IL-6. Reactive oxygen species (ROS) level increased and the oxidation/redox system was disturbed in LPS-stimulated cardiomyocytes, as evident from the decrease in superoxide dismutase activity and an increase in reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and malondialdehyde level. CTRP12 overexpression decreased the increasing level of ROS and ameliorated the unbalance in the oxidation/redox system in LPS-stimulated cardiomyocytes. The viability of cardiomyocytes decreased after LPS stimulation, and the cells underwent apoptosis. CTRP12-overexpressing cardiomyocytes showed a decrease in the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)positive cells, and the ratio of B cell lymphoma (Bcl)-1/Bax in these cells was recovered. In comparison with the control group, LPS-stimulated cardiomyocytes showed reduced expression of nuclear factor E2-related factor 2 (NRF2), while CTRP12-overexpressing cardiomyocytes showed elevated NRF2 expression. Smallinterfering RNA-mediated silencing of NRF2 expression in cardiomyocytes resulted in the inhibition of the protective effects of CTRP12. Thus, CTRP12 ameliorated injury in LPS-stimulated cardiomyocytes in an NRF2-dependent manner.

CTRP12 ameliorates atherosclerosis by promoting cholesterol efflux and inhibiting inflammatory response via the miR-155-5p/LXRα pathway

“…Adiponectin is known to protect against atherosclerosis in animal models 32,33 . Although CTRP12 was reported to participate in the occurrence and development of cardiovascular disease [22][23][24] , its role in atherogenesis is still largely unknown. Our in vivo experiments demonstrated that aortic plaque burden was significantly lower in apoE −/− mice overexpressing CTRP12 than that in apoE −/− littermates.…”

“…of pro-inflammatory cytokines 58 . Treatment with recombinant CTRP12 decreases the expression of MCP-1, TNFα and IL-6 in LPS-treated macrophages 59 .…”

“…M1 macrophages secrete pro-inflammatory cytokines and promote the development of atherosclerosis, while M2 macrophages contribute to inflammation resolution and play an atheroprotective role 56 , 57 . In LPS-stimulated cardiomyocytes, overexpression of CTRP12 blocks the generation and release of pro-inflammatory cytokines 58 . Treatment with recombinant CTRP12 decreases the expression of MCP-1, TNF-α and IL-6 in LPS-treated macrophages 59 .…”

“…C1q tumor necrosis factor-related protein 12 (CTRP12), also known as adipolin, is a newly discovered adipokine and a conserved paralog of adiponectin 21 . Overexpression of CTRP12 was shown to ameliorate cardiomyocyte injury induced by LPS 22 . Deletion of CTRP12 in mice aggravates neointimal thickening after vascular injury 23 .…”

CTRP12 inhibits triglyceride synthesis and export in hepatocytes by suppressing HNF‐4α and DGAT2 expression

“…Initial gain‐of‐function studies in mice have revealed antidiabetic [12] and anti‐inflammatory [27] activities of CTRP12. Recent studies also implicated a protective role of CTRP12 in the cardiovascular system [40,41]. In the context of metabolism, CTRP12 acts through insulin‐dependent and insulin‐independent pathways to control glucose metabolism in liver and adipose tissue [12].…”