Dataset Information

Age-independent Cardiac Protection by Pharmacological Activation of Beclin-1 During Endotoxemia and Its Association with Energy Metabolic Reprograming in Myocardium — A Targeted Metabolomics Study

ABSTRACT: Background: We previously showed that Beclin-1-dependent autophagy is cardiac protective in a rodent model of endotoxemia using young adult mice. In this report, we compared the potential therapeutic effects of pharmacological Beclin-1 activating peptide, TB-peptide, on the cardiac outcomes of young adult and aged mice during endotoxemia. We further examined alterations in myocardial metabolism induced by lipopolysaccharide (LPS) challenge with and without the TB-peptide treatment. Methods and Results: C57BL/6J mice of 10-week and 24-month-old were challenged by LPS at doses at which cardiac dysfunction occurred. Following the treatment of TB-peptide or control vehicle, heart contractility, circulating cytokines, and myocardial autophagy were evaluated. A targeted metabolomics assay was applied to analyze cardiac metabolism. TB-peptide boosted autophagic response, attenuated cytokine production, and improved cardiac performance in both young and aged mice during endotoxemia. A targeted metabolomics assay was designed to detect a pool of 361 known metabolites, of which 156 were detected in at least one of the heart tissue samples. LPS-induced impairments were found in glucose and amino acid (AA) metabolisms in mice of all ages, and TB-peptide provided ameliorative effects to rescue these alterations. However, lipid metabolites were upregulated in the young group but moderately downregulated in the aged by LPS, suggesting an age-dependent response. TB-peptide mitigated LPS-mediated trend of lipids in the young mice but provided little effect on the aged ones. Conclusion: Pharmacological activation of Beclin-1 by TB-peptide protects the heart in both young and aged population during endotoxemia, suggest a therapeutic potential for sepsis-induced cardiomyopathy. Metabolomics analysis suggests that this age-independent protection by TB-peptide is associated with reprograming of energy production via glucose and AA metabolisms.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Heart

DISEASE(S): Endotoxemia

SUBMITTER: Qun Zang

PROVIDER: ST002178 | MetabolomicsWorkbench | Mon May 23 00:00:00 BST 2022

REPOSITORIES: MetabolomicsWorkbench

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	mwtab	Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Caloric Restriction in Leptin Deficiency Worsens Myocardial Steatosis: Failure to Upregulate PPAR gamma and Thermogenic Glyecrolipid/Fatty Acid Cycling Growing evidence supports an anti-lipotoxic role for leptin in preventing inappropriate peripheral tissue lipid deposition. Obese, leptin deficient ob/ob mice develop left ventricular (LV) hypertrophy and myocardial steatosis with increased apoptosis and decreased longevity. Here we investigated the cardiac effects of caloric restriction in leptin deficiency. Echocardiography was performed on C57Bl/6 wild-type mice (WT) and 7-month-old ob/ob mice fed ad lib, leptin-repleted (LR-ob/ob), or calorie-restricted (CR-ob/ob) for four weeks. Ventricular tissue was examined by electron microscopy (EM), mitochondrial coupling assay, and microarray expression profiling. LR and CR-ob/ob mice showed decreased body weight, heart weight, and LV wall thickness compared to ad lib ob/ob mice. LV fractional shortening was decreased in ad lib ob/ob mice, but restored to WT levels in LR and CR groups. However, EM revealed severe cardiac steatosis in the CR-ob/ob group compared to only moderate steatosis in ad lib ob/ob . Despite marked cardiac steatosis, CR (like LR) restored mitochondrial coupling to WT levels. CR up-regulated genes associated with oxidative stress and cell death, changes suggestive of cardiac lipotoxicity. LR, but not CR was shown to induce core genes involved in glycerolipid/free fatty acid cycling, a highly thermogenic pathway that can reduce intracellular lipid stores. LR, but not CR up-regulated and restored PGC1 and PPARto wild type levels; CR paradoxically further suppressed cardiac PPAR. Thus, leptin is essential in protecting the heart from lipotoxicity, and the inability to up-regulate the thermogenic glycerolipid/free fatty acid cycling pathway may impair the response of leptin deficient animals to the lipotoxic stress of calorie restriction. 6 month aged ob/ob mice were either leptin repleted with osmotic mini-pumps, calorie restricted to match the caloric intake of the leptin repleted mice, or fed ad lib for one month. 6-8 month C57Bl/6J mice were aged to serve as controls.

Project description:To identify in vivo new cardiac SRF target genes and to study the response of these novel genes to SRF overexpression, we employed a cardiac-specific, transgenic mouse model that has a phenotype in young adulthood which resembles that of the typically aged heart. Using this “cardiac aging” model, we identified 207 genes that are important to cardiac function that were differentially expressed in vivo. Among them, 192 genes had SRF binding motifs (56 with CArG and 136 with CArG-like elements) in their promoter region. Fifty-one of 56 genes with classic CArG elements were not previously reported. These SRF target genes were grouped into 12 categories based on their function. It was observed that genes associated with cardiac energy metabolism shifted toward that of carbohydrate metabolism and away from that of fatty acid metabolism. The expression of genes that are involved in transcription and ion regulation were decreased, but expression of cytoskeletal genes were significantly increased. Using public databases of mouse models of stress, we also found that altered expression of the SRF target genes occurred in these hearts as well. Thus, SRF target genes are actively regulated under various physiological and pathological conditions, including hemodynamic stress. The mild elevation of SRF protein in the rodent heart that is observed during typical adult aging may have a major impact on many SRF target genes, thereby affecting cardiac structure and performance. In addition, these results could help to enhance our understanding of SRF regulation of cellular processes, including metabolic and cytoskeletal function. The generation and characterization of transgenic mice with mild cardiac-specific overexpression of SRF was previously reported (Zhang et al., 2003). At 6 months of age, the transgenic mice manifested cardiac changes suggestive of an “aged heart” (Zhang et al., 2003). Therefore, 6-month-old transgenic and non-transgenic mice were used in this study. Cardiac gene expression in SRF Tg heart was compared to that of wild-type mice.

Project description:VEGF family members are important regulators of vascular functions. Promoting VEGFA signalling in aged mice has been shown to delay various aging phenotypes and extend the survival of aged mice. Although there is profound knowledge on functions of VEGFA, VEGFB has not been investigated in the context of cardiac aging. Our RNA data of aged mouse hearts revealed significant downregulation of Vegfb in the heart, specifically in endothelial cells and cardiomyocytes, while VEGFB expression was reduced in endothelial cells, fibroblasts and cardiomyocytes in aged human hearts. By contrast, VEGFB expression was exclusively reduced in cardiomyocytes of patients with cardiac hypertrophy. Hence, we investigated whether Vegfb gene therapy can revert age-dependent cardiac pathologies. We overexpressed Vegfb186, the soluble VEGFB isoform, via AAV9 vector transduction into 18-month-old C57Bl/6J male mice. AAV9-Vegfb treatment prevented progression age-related diastolic dysfunction and decreased cardiac fibrosis. We further found a rescue of aging-related left ventricular denervation in the hearts of AVV9-Vegfb treated old mice which was associated with an increase in heart rate variability. However, heart to body weight ratio and cardiomyocyte hypertrophy were increased in the AAV9-Vegfb treated mouse hearts, without alteration of cardiac systolic or diastolic function. Histological and transcriptomic analyses revealed that VEGFB186 induces compensatory cardiac hypertrophy which was accompanied by a rescued length-width-ratio, reduced fibrosis and the absence of cardiac inflammation. Cardiac single-nuclei RNA sequencing further suggested that AAV9-Vegfb treatment affects cardiac hypertrophy putatively via STAT3 which was validated in vitro. In conclusion, our data reveals that Vegfb overexpression partially reverses pathological alterations in the aging heart. Despite the overall improvement of the age-related cardiac phenotype, the AAV9-Vegfb-mediated induced cardiac hypertrophy which might reflect protective hypertrophy.

Dataset Information

Age-independent Cardiac Protection by Pharmacological Activation of Beclin-1 During Endotoxemia and Its Association with Energy Metabolic Reprograming in Myocardium — A Targeted Metabolomics Study

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets