Imeglimin prevents heart failure with preserved ejection fraction by recovering the impaired unfolded protein response in mice subjected to cardiometabolic stress

Kitakata, Hiroki; Endo, Jin; Hashimoto, Shun; Mizuno, Erika; Moriyama, Hidenori; Shirakawa, Kohsuke; Goto, Shinichi; Katsumata, Yoshinori; Fukuda, Keiichi; Sano, Motoaki

doi:10.1016/j.bbrc.2021.07.090

Cited by 43 publications

(36 citation statements)

References 36 publications

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“…Studies in the “two-hit” mouse model of HFpEF suggest that the Unfolded Protein Response (UPR) governs lipid accumulation and contractile performance 29 , 37 . Targeting UPR by Imeglimin prevents metabolic and cardiac abnormalities in the model 38 .…”

Section: Discussionmentioning

confidence: 99%

Sex differences in heart mitochondria regulate diastolic dysfunction

et al. 2022

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Heart failure with preserved ejection fraction (HFpEF) exhibits a sex bias, being more common in women than men, and we hypothesize that mitochondrial sex differences might underlie this bias. As part of genetic studies of heart failure in mice, we observe that heart mitochondrial DNA levels and function tend to be reduced in females as compared to males. We also observe that expression of genes encoding mitochondrial proteins are higher in males than females in human cohorts. We test our hypothesis in a panel of genetically diverse inbred strains of mice, termed the Hybrid Mouse Diversity Panel (HMDP). Indeed, we find that mitochondrial gene expression is highly correlated with diastolic function, a key trait in HFpEF. Consistent with this, studies of a “two-hit” mouse model of HFpEF confirm that mitochondrial function differs between sexes and is strongly associated with a number of HFpEF traits. By integrating data from human heart failure and the mouse HMDP cohort, we identify the mitochondrial gene Acsl6 as a genetic determinant of diastolic function. We validate its role in HFpEF using adenoviral over-expression in the heart. We conclude that sex differences in mitochondrial function underlie, in part, the sex bias in diastolic function.

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Section: Discussionmentioning

confidence: 99%

Sex differences in heart mitochondria regulate diastolic dysfunction

et al. 2022

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“…In rat neonatal cardiomyocytes, CHIP expression alleviated myocardial lipid formation, and either the loss of FoxO1 or the over-expression of Xbp1s eliminates the HfpEF phenotype in mouse models [90]. In a complementary study, treating mice with Imeglimin restored cardiac CHIP expression, decreased FoxO1 levels, and decreased fatty acid synthase [91], demonstrating a protective role for CHIP against apoptosis and oxidative stress.…”

Section: Cardioprotectionmentioning

confidence: 90%

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Altınok

Sanchez‐Hodge

Stewart

et al. 2021

Cells

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Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintain protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensure cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, with a concentration on cardioprotection, neuroprotection, cancer, and autoimmune diseases. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.

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“…In rat neonatal cardiomyocytes, CHIP expression alleviated myocardial lipid formation, and either the loss of FoxO1 or the over-expression of Xbp1s eliminates the HfpEF phenotype in mouse models [71]. In a complementary study, treating mice with Imeglimin restored cardiac CHIP expression, decreased FoxO1 levels, and decreased fatty acid synthase [72], demonstrating a protective role for CHIP against apoptosis and oxidative stress.…”

Section: Cardioprotectionmentioning

confidence: 90%

With or Without You: Co-chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

Altınok¹,

Sanchez‐Hodge²,

Stewart³

et al. 2021

Preprint

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Heat shock proteins (HSPs) are a family of molecular chaperones that regulate essential protein refolding and triage decisions to maintaining protein homeostasis. Numerous co-chaperone proteins directly interact and modify the function of HSPs, and these interactions impact the outcome of protein triage, impacting everything from structural proteins to cell signaling mediators. The chaperone/co-chaperone machinery protects against various stressors to ensuring cellular function in the face of stress. However, coding mutations, expression changes, and post-translational modifications of the chaperone/co-chaperone machinery can alter the cellular stress response. Importantly, these dysfunctions appear to contribute to numerous human diseases. Therapeutic targeting of chaperones is an attractive but challenging approach due to the vast functions of HSPs, likely contributing to the off-target effects of these therapies. Current efforts focus on targeting co-chaperones to develop precise treatments for numerous diseases caused by defects in protein quality control. This review focuses on the recent developments regarding selected HSP70/HSP90 co-chaperones, focusing on cardioprotection, neuroprotection, and cancer. We also discuss therapeutic approaches that highlight both the utility and challenges of targeting co-chaperones.

show abstract

Imeglimin prevents heart failure with preserved ejection fraction by recovering the impaired unfolded protein response in mice subjected to cardiometabolic stress

Cited by 43 publications

References 36 publications

Sex differences in heart mitochondria regulate diastolic dysfunction

Sex differences in heart mitochondria regulate diastolic dysfunction

With or without You: Co-Chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

With or Without You: Co-chaperones Mediate Health and Disease by Modifying Chaperone Function and Protein Triage

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