Hepatocyte-specific Selenop knockout in mice attenuated cardiac hypertrophy, dysfunction, and fibrosis in response to pressure overload compared to wild-type mice.
Does hepatocyte-specific Selenop knockout attenuate cardiac hypertrophy and dysfunction in response to pressure overload in mice?
Hepatocyte-specific deletion of Selenoprotein P attenuates cardiac hypertrophy, dysfunction, and fibrosis in response to pressure overload in mice, suggesting a maladaptive role in heart failure progression via cardio-hepatic interaction.
Abstract Background In heart failure, blood flow is reduced due to pump dysfunction, and this leads to dysfunction of energy metabolism in tissues and organs throughout the body. The liver is the largest organ in the human body and plays a central role in lipid and glucose metabolism. Selenoprotein P (Selenop), the most abundant circulating selenoprotein secreted by the liver, contributes to insulin resistance and hyperglycemia in type 2 diabetes. In heart failure patients, blood levels of Selenop were significantly higher compared to controls, and a decrease in Selenop levels was linked to better cardiac outcomes, including reduced cardiac death and worsening heart failure. However, a cohort study in the general population showed that lower Selenop levels were associated with a higher risk of developing heart failure. There is no consistent evidence on the role of Selenop in the pathogenesis of heart failure. Purpose We investigated the role of Selenop in regulating cardiac hypertrophy and function in response to pressure overload. Methods and Results Tysis showed that TAC activates the IL-6 and TGF-β pathways of the FoxO signaling pathway in the liver. We generated hepatocyte-specific Selenop knockout (Hep-Selenop KO) mice. There were no differences in the baseline cardiac phenotype between the Hep-Selenop KO mice and WT mice. However, TAC-induced increases in left ventricular weight/total body weight were significantly lower in the Hep-Selenop KO mice than in the WT mice. TAC-induced increases in lung weight/total body weight were also lower in the Hep-Selenop KO mice than in the WT mice. The upregulation of hypertrophy-related genes induced by TAC was significantly lower in Hep-Selenop KO mice than in WT mice. These results suggest that Selenop gene deficiency in the liver suppresses cardiac remodeling due to pressure overload. As receptors for the uptake of Selenop, LRP (LDL Receptor Related Protein 1) 1, LRP2, and LRP8 have been reported. Single-cell RNA sequencing analysis in hearts using the Human Cell Atlas database revealed that LRP1 is expressed in cardiac fibroblasts. RT-PCR analysis also showed that LRP1 mRNA expression was significantly higher in fibroblasts than in cardiomyocytes. Conclusions These results suggest that cardiac pressure overload induced hepatic expression of Selenop and the absence of endogenous Selenop attenuated cardiac hypertrophy, dysfunction and fibrosis in response to pressure overload in mice. Selenop possibly plays a maladaptive role against progression of heart failure through the cardio-hepatic interaction.
Usui et al. (2025) studied Heart failure. Hepatocyte-specific Selenop knockout vs. Wild-type (WT) mice was evaluated on Cardiac hypertrophy and remodeling (left ventricular weight/total body weight). Hepatocyte-specific Selenop knockout in mice attenuated cardiac hypertrophy, dysfunction, and fibrosis in response to pressure overload compared to wild-type mice.
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