Melatonin reduces cardiac remodeling and improves survival in rats with isoproterenol‐induced heart failure

Šimko, Fedor; Bednarova, Kristina Repova; Krajcirovicova, Kristina; Hrenak, Jaroslav; Celec, Peter; Kamodyová, Natália; Gajdosechova, Lucia; Zórad, Štefan; Adamcová, Michaela

doi:10.1111/jpi.12154

Cited by 79 publications

(74 citation statements)

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Section: Discussionmentioning

confidence: 99%

“…The usefulness of melatonin treatment for cardiovascular diseases has been reported . Melatonin supplementation protected against pathological cardiac remodeling induced by transverse aortic constriction and isoproterenol, and melatonin prevented mitochondrial fission and improved cardiac function in mice with diabetes through the SIRT1‐PGC1α pathway . Administration of melatonin in AMI patients with ST elevation, who presented early after symptom onset, was associated with a significant reduction in the infarct size and remodeling after primary percutaneous coronary intervention .…”

Section: Discussionmentioning

confidence: 99%

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Plasma levels of melatonin in dilated cardiomyopathy

Misaka

Yoshihisa

Yokokawa

et al. 2019

Journal of Pineal Research

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Background Melatonin is a multifunctional indolamine and has a cardioprotective role in a variety of cardiovascular processes via antioxidant, anti‐inflammatory, antihypertensive, antithrombotic, and antilipemic effects. It has been reported that lower levels of circulating melatonin are significantly associated with a higher risk of acute myocardial infarction (AMI) and later cardiac remodeling. However, levels of melatonin in patients with dilated cardiomyopathy (DCM) and associations between melatonin levels and cardiac function remain unclear. Methods and Results We measured and compared plasma levels of melatonin in 61 control subjects, 81 AMI patients, and 77 DCM patients. Plasma levels of melatonin were progressively decreased from 71.9 pg/mL in the control group to 52.6 pg/mL in the DCM group and 21.9 pg/mL in the AMI group. Next, we examined associations of melatonin levels with parameters of laboratory data, echocardiography, and right‐heart catheterization. In the DCM patients, circulating melatonin showed significant correlations with both high‐sensitivity troponin T ( R = −0.422, P < 0.001) and cardiac output ( R = 0.431, P = 0.003), but not with B‐type natriuretic peptide (BNP), left ventricular ejection fraction (LVEF), pulmonary artery wedge pressure, or pulmonary artery pressure. Conclusion Patients with not only AMI but also DCM had lower circulating melatonin levels. Circulating melatonin levels appear to correlate with myocardial injury and cardiac output in DCM patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Plasma levels of melatonin in dilated cardiomyopathy

Misaka

Yoshihisa

Yokokawa

et al. 2019

Journal of Pineal Research

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“…1,2,33 This study identified that expression of USP4 was downregulated in human failing heart samples and in a murine model of cardiac hypertrophy induced by pressure overload. Adenovirus-mediated gainand loss-of-function approaches indicated that decreased expression of endogenous USP4 promoted myocyte hypertrophy induced by Ang II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of Ang II.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin-Specific Protease 4 Is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Zhao

Gao

et al. 2016

Hypertension

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Abstract-Dysregulation of the ubiquitin proteasome system components ubiquitin ligases and proteasome plays an important role in the pathogenesis of cardiac hypertrophy. However, little is known about the role of another ubiquitin proteasome system component, the deubiquitinating enzymes, in cardiac hypertrophy. Here, we revealed a crucial role of ubiquitin specific protease 4 (USP4), a deubiquitinating enzyme prominently expressed in the heart, in attenuating pathological cardiac hypertrophy and dysfunction. USP4 levels were consistently decreased in human failing hearts and in murine hypertrophied hearts. Adenovirus-mediated gain-and loss-of-function approaches indicated that deficiency of endogenous USP4 promoted myocyte hypertrophy induced by angiotensin II in vitro, whereas restoration of USP4 significantly attenuated the prohypertrophic effect of angiotensin II. To corroborate the role of USP4 in vivo, we generated USP4 global knockout mice and mice with cardiac-specific overexpression of USP4. Consistent with the in vitro study, USP4 depletion exacerbated the hypertrophic phenotype and cardiac dysfunction in mice subjected to pressure overload, whereas USP4 transgenic mice presented ameliorated pathological cardiac hypertrophy compared with their control littermates. Molecular analysis revealed that USP4 deficiency augmented the activation of the transforming growth factor β-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling in response to hypertrophic stress, and blockage of TAK1 activation abolished the pathological effects of USP4 deficiency in vivo. These findings provide the first evidence for the involvement of USP4 in cardiac hypertrophy, and shed light on the therapeutic potential of targeting USP4 in the treatment of cardiac hypertrophy. promotes ionizing radiation-induced cell apoptosis by specifically reducing p53 expression. 13 Of note, USP4 is a putative proto-oncogene, which promotes epithelial to mesenchymal transition and breast cancer cell migration. 18 Interestingly, mounting evidence supports pivotal roles of proto-oncogenes in modulating cardiac hypertrophy, 19,20 indicating a potential involvement of USP4 in cardiac hypertrophy. We therefore posited that USP4, a DUB prominently expressed in the heart, might be a potential signaling regulator implicated in cardiac hypertrophy.In this study, we observed reduced levels of USP4 in hearts from patients with dilated cardiomyopathy and in animal models of cardiac hypertrophy induced by pressure overload. By subjecting USP4 knockout mice and transgenic mice with cardiac-specific USP4 overexpression to aortic banding (AB), we observed that USP4 deficiency aggravated hypertrophic growth and cardiac dysfunction. Conversely, restoration of USP4 level remarkably protected the heart against pathological hypertrophy. Mechanistically, the beneficial effect of USP4 was largely dependent on the blockade of the transforming growth factor β-activated kinase 1 (TAK1)-(JNK1/2)/P38 signaling. Materials and MethodsThe animal protocol was approved by the Instit...

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“…The rats were divided into four groups (n ¼ 5) randomly: 1) normoxia þ saline (NOR þ SAL), 2) normoxia þ melatonin (NOR þ MEL), 3) CIH þ saline (CIH þ SAL), and 4) CIH þ melatonin (CIH þ MEL). The rats were treated with CIH or normoxia and received melatonin (SigmaeAldrich, USA; 10 mg/kg body weight) [24,25] or the same dose of saline by daily intraperitoneal (ip) injection. During CIH treatment, rats were housed in controlled oxygen-concentration chambers (OxyCycler A84; Biospherix, Redfield, NY, USA).…”

Section: Animal Model and Experimental Protocolmentioning

confidence: 99%