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Load-Dependent Changes in Left Ventricular Gene Expression in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure (2 weeks heart failure, 4 weeks reversal)

ABSTRACT: Wild type, female, C57BL/6 mice were subjected to sham (n=6) surgery, or TAC + MI to cause progressive LV remodeling (n=12). At 2wks post-TAC, one group of mice underwent de-banding (HF-DB, n=6), whereas in a second group of mice the band remained intact (HF; n = 6). LV remodeling was evaluated by 2D echocardiography at 14 days post-TAC+MI , and 4 wks post-debanding. At 6 wks the hearts were excised and analyzed for changes in gene expression using transcriptional profiling. e-banding in the HF-DB mice resulted in normalization of LV volumes and LV mass, and normalization of cardiac myocyte hypertrophy at 6wks, without significant changes in myofibrillar collagen in the HF and HF-DB mice. Both LV ejection fraction (LVEF) and LV radial strain improved numerically following de-banding; however, both measurements remained significantly depressed in the HF-DB mice compared to sham, and were not significantly different from HF mice at 6wks. Reverse LV remodeling in the HF-DB mouse hearts was accompanied by a partial (80%) normalization of the genes that became dysregulated during LV remodeling, whereas 20% of genes remained persistently dysregulated following reverse LV remodeling.

ORGANISM(S): Mus musculus

PROVIDER: GSE107568 | GEO | 2017/12/14

SECONDARY ACCESSION(S): PRJNA420797

REPOSITORIES: GEO

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Project description:BACKGROUND: Heart failure (HF) is one of the leading causes of mortality worldwide. Extracellular vesicles (EVs) including small EVs, or exosomes and their molecular cargo are known to modulate cell to cell communication during multiple cardiac diseases. However, the role of systemic EV biogenesis inhibition in the models of HF is not well documented and remains unclear. METHODS: We investigated the role of circulating exosomes during cardiac dysfunction and remodeling in a mouse transverse aortic constriction (TAC) model of HF. Importantly, we investigate the efficacy of Tipifarnib (Tip), a recently identified exosome biogenesis inhibitor that targets the critical proteins (Rab27a, nSmase2 and Alix) involved in exosome biogenesis for this mouse model of HF. In this study, 10-week-old male mice underwent TAC surgery, were randomly assigned to groups with and without Tip treatment (10 mg/kg three times/week) and monitored for 8 weeks and a comprehensive assessment was conducted through performed echocardiographic, histological, and biochemical studies. RESULTS: TAC significantly elevated circulating plasma exosomes and markedly increased cardiac left ventricular (LV) dysfunction, cardiac hypertrophy, and fibrosis. Furthermore, injection of plasma exosomes from TAC mice induced LV dysfunction and cardiomyocyte hypertrophy in uninjured mice without TAC. On the contrary, treatment of Tip in TAC mice reduced circulating exosomes to baseline and remarkably improved LV functions, hypertrophy, and fibrosis. Tip treatment also drastically altered the miRNA profile of circulating post-TAC exosomes, including miR331-5p which was highly downregulated both in TAC circulating exosomes and in TAC cardiac tissue. Mechanistically, miR331-5p is crucial for inhibiting fibroblast-to-myofibroblast transition by targeting HOXC8, a critical regulator of fibrosis. Tipifarnib treatment in TAC mice upregulated the expression of miR331-5p that acts as potent repressor for one of the fibrotic mechanisms mediated by HOXC8. CONCLUSIONS: Our study underscores the pathological role of exosomes in HF and fibrosis in response to pressure overload. Tipifarnib mediated inhibition of exosome biogenesis and cargo sorting may serve as a viable strategy to prevent progressive cardiac remodeling to HF.

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Load-Dependent Changes in Left Ventricular Gene Expression in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure (2 weeks heart failure, 4 weeks reversal)

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