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Chronic kidney disease induces left ventricular overexpression of the pro-hypertrophic microRNA-212.

ABSTRACT: Chronic kidney disease (CKD) is a public health problem that increases the risk of cardiovascular morbidity and mortality. Heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction is a common cardiovascular complication of CKD. MicroRNA-212 (miR-212) has been demonstrated previously to be a crucial regulator of pathologic LVH in pressure-overload-induced heart failure via regulating the forkhead box O3 (FOXO3)/calcineurin/nuclear factor of activated T-cells (NFAT) pathway. Here we aimed to investigate whether miR-212 and its hypertrophy-associated targets including FOXO3, extracellular signal-regulated kinase 2 (ERK2), and AMP-activated protein kinase (AMPK) play a role in the development of HFpEF in CKD. CKD was induced by 5/6 nephrectomy in male Wistar rats. Echocardiography and histology revealed LVH, fibrosis, preserved systolic function, and diastolic dysfunction in the CKD group as compared to sham-operated animals eight and/or nine weeks later. Left ventricular miR-212 was significantly overexpressed in CKD. However, expressions of FOXO3, AMPK, and ERK2 failed to change significantly at the mRNA or protein level. The protein kinase B (AKT)/FOXO3 and AKT/mammalian target of rapamycin (mTOR) pathways are also proposed regulators of LVH induced by pressure-overload. Interestingly, phospho-AKT/total-AKT ratio was increased in CKD without significantly affecting phosphorylation of FOXO3 or mTOR. In summary, cardiac overexpression of miR-212 in CKD failed to affect its previously implicated hypertrophy-associated downstream targets. Thus, the molecular mechanism of the development of LVH in CKD seems to be independent of the FOXO3, ERK1/2, AMPK, and AKT/mTOR-mediated pathways indicating unique features in this form of LVH.

SUBMITTER: Sarkozy M

PROVIDER: S-EPMC6362219 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Chronic kidney disease induces left ventricular overexpression of the pro-hypertrophic microRNA-212.

Sárközy Márta M Gáspár Renáta R Zvara Ágnes Á Siska Andrea A Kővári Bence B Szűcs Gergő G Márványkövi Fanni F Kovács Mónika G MG Diószegi Petra P Bodai László L Zsindely Nóra N Pipicz Márton M Gömöri Kamilla K Kiss Krisztina K Bencsik Péter P Cserni Gábor G Puskás László G LG Földesi Imre I Thum Thomas T Bátkai Sándor S Csont Tamás T

Scientific reports 20190204 1

Chronic kidney disease (CKD) is a public health problem that increases the risk of cardiovascular morbidity and mortality. Heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction is a common cardiovascular complication of CKD. MicroRNA-212 (miR-212) has been demonstrated previously to be a crucial regulator of pathologic LVH in pressure-overload-induced heart failure via regulating the forkhead box O3 (FOXO3)/calcineuri ...[more]

PMID: 30718600

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Project description:Background: A deleterious, late-onset side effect of thoracic radiotherapy is the development of radiation-induced heart disease (RIHD). It covers a spectrum of cardiac pathology including also heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction. MicroRNA-212 (miR-212) is a crucial regulator of pathologic LVH via FOXO3-mediated pathways in pressure-overload-induced heart failure. We aimed to investigate whether miR-212 and its selected hypertrophy-associated targets play a role in the development of RIHD. Methods: RIHD was induced by selective heart irradiation (50 Gy) in a clinically relevant rat model. One, three, and nineteen weeks after selective heart irradiation, transthoracic echocardiography was performed to monitor cardiac morphology and function. Cardiomyocyte hypertrophy and fibrosis were assessed by histology at week 19. qRT-PCR was performed to measure the gene expression changes of miR-212 and forkhead box O3 (FOXO3) in all follow-up time points. The cardiac transcript level of other selected hypertrophy-associated targets of miR-212 including extracellular signal-regulated kinase 2 (ERK2), myocyte enhancer factor 2a (MEF2a), AMP-activated protein kinase, (AMPK), heat shock protein 40 (HSP40), sirtuin 1, (SIRT1), calcineurin A-alpha and phosphatase and tensin homolog (PTEN) were also measured at week 19. Cardiac expression of FOXO3 and phospho-FOXO3 were investigated at the protein level by Western blot at week 19. Results: In RIHD, diastolic dysfunction was present at every time point. Septal hypertrophy developed at week 3 and a marked LVH with interstitial fibrosis developed at week 19 in the irradiated hearts. In RIHD, cardiac miR-212 was overexpressed at week 3 and 19, and FOXO3 was repressed at the mRNA level only at week 19. In contrast, the total FOXO3 protein level failed to decrease in response to heart irradiation at week 19. Other selected hypertrophy-associated target genes failed to change at the mRNA level in RIHD at week 19. Conclusions: LVH in RIHD was associated with cardiac overexpression of miR-212. However, miR-212 seems to play a role in the development of LVH via FOXO3-independent mechanisms in RIHD. As a central regulator of pathologic remodeling, miR-212 might become a novel target for RIHD-induced LVH and heart failure.

Project description:Development of right ventricular (RV) hypertension eventually contributes to RV and left ventricular (LV) myocardial fibrosis and dysfunction. The molecular mechanisms are not fully elucidated.Pulmonary artery banding was used to induce RV hypertension in rats in vivo. Then, we evaluated cardiac function and regional remodeling 6 weeks after pulmonary artery banding. To further elucidate mechanisms responsible for regional cardiac remodeling, we also mimicked RV hypertensive stress by cyclic mechanical stretching applied to confluent cultures of cardiac fibroblasts, isolated from the RV free wall, septal hinge points, and LV free wall. Echocardiography and catheter evaluation demonstrated that rats in the pulmonary artery banding group developed RV hypertension with leftward septal displacement, LV compression, and increased LV end-diastolic pressures. Picrosirius red staining indicated that pulmonary artery banding induced marked RV fibrosis and dysfunction, with prominent fibrosis and elastin deposition at the septal hinge points but less LV fibrosis. These changes were associated with proportionally increased expressions of integrin-?1 and profibrotic signaling proteins, including phosphorylated Smad2/3 and transforming growth factor-?1. Moreover, mechanically stretched fibroblasts also expressed significantly increased levels of ?-smooth muscle actin, integrin-?1, transforming growth factor-?1, collagen I deposition, and wrinkle formation on gel assays, consistent with myofibroblast transformation. These changes were not observed in parallel cultures of mechanically stretched fibroblasts, preincubated with the integrin inhibitor (BTT-3033).Experimentally induced RV hypertension triggers regional RV, hinge-point, and LV integrin ?1-dependent mechanotransduction signaling pathways that eventually trigger myocardial fibrosis via transforming growth factor-?1 signaling. Reduced LV fibrosis and preserved global function, despite geometrical and pressure aberrations, suggest a possible elastin-mediated protective mechanism at the septal hinge points.

Project description:BackgroundThe right ventricle (RV) in hypertrophic cardiomyopathy (HCM) tends to be neglected, as previous efforts have predominantly focused on examining the prognostic value of left ventricular (LV) abnormalities. The objectives of this study were to assess RV function in HCM, changes over time, and association with clinical outcomes.MethodsTwo hundred and ninety HCM patients with preserved LV ejection fraction (LVEF ≥ 55%) and 30 age- and sex-matched controls underwent cardiovascular magnetic resonance (CMR). All patients were followed up for clinical events for a median duration of 4.4 years. Sixty-three patients had a follow-up CMR undertaken at a median interval of 5.4 years. Main study measures and outcomes were RV function (RV ejection fraction (RVEF) and RV strain) at baseline, temporal changes in RV function over time and prognostic value of RV dysfunction for predicting cardiovascular outcomes in HCM.ResultsWhen compared to controls, HCM patients exhibited lower RV and LV peak global longitudinal systolic strains on feature-tracking analysis of cine images, while RVEF and LVEF were within the normal range. On follow-up CMR, both RV and LV strain parameters decreased over time. RVEF decreased at follow-up (65 ± 7% to 62 ± 7%, P < 0.001) but the change in LVEF was not significant (68 ± 10% to 66 ± 8%, P = 0.30). On clinical follow up, reduced RVEF was an independent predictor of non-sustained ventricular tachycardia (NSVT) [HR 1.10 (95% CI 1.06-1.15), P < 0.001] and composite cardiovascular events (NSVT, stroke, heart failure hospitalisation and cardiovascular death) [HR 1.07 (95% CI 1.03-1.10), P < 0.001]. RV longitudinal strain was an independent predictor of NSVT [HR 1.05 (95% CI 1.01-1.09), P = 0.029]. Patients with RVEF < 55% showed an increased risk of NSVT and composite cardiovascular events. In contrast, LVEF and LV global longitudinal strain were not predictive of such events on multivariable analysis.ConclusionsIn HCM, RV function, including RV strain, and LV strain decrease over time despite preserved LVEF. Reduction in RV but not LV function is associated with adverse cardiovascular outcomes. Assessing RV function in early HCM disease might have a role in risk stratification to prevent future cardiovascular events.

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Chronic kidney disease induces left ventricular overexpression of the pro-hypertrophic microRNA-212.

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Chronic kidney disease induces left ventricular overexpression of the pro-hypertrophic microRNA-212.

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