Inhibition of miR-208b improves cardiac function in titin-based dilated cardiomyopathy

Zhou, Qifeng; Schötterl, Sonja; Backes, Daniel; Brunner, Ewald Johannes; Hahn, Johannes-Martin; Ionesi, Elena; Aidery, Parwez; Sticht, Carsten; Labeit, Siegfried; Kandolf, Reinhard; Gawaz, Meinrad; Gramlich, Michael

doi:10.1016/j.ijcard.2016.12.171

Cited by 42 publications

(23 citation statements)

References 35 publications

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“…Hence, regression of hypertension-induced cardiac remodeling can improve the prognosis of patients with hypertension. The contribution of miRs in the cardiomyopathies such as ischemic heart disease, hypertrophic cardiomyopathy, and dilated cardiomyopathy has been shown [29][30][31]. However, the impact of miR-21 as well as other miRs on the pathogenesis of HHD, which is one of the most important hypertensioninduced organ damages is still unclear.…”

Section: Discussionmentioning

confidence: 99%

The association between microRNA-21 and hypertension-induced cardiac remodeling

et al. 2020

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Hypertension is a major public health problem among the aging population worldwide. It causes cardiac remodeling, including hypertrophy and interstitial fibrosis, which leads to development of hypertensive heart disease (HHD). Although microRNA-21 (miR-21) is associated with fibrogenesis in multiple organs, its contribution to cardiac remodeling in hypertension is poorly understood. Circulating miR-21 level was higher in patients with HHD than that in the control subjects. It also positively correlated with serum myocardial fibrotic markers. MiR-21 expression levels were significantly upregulated in the mice hearts after angiotensin II (Ang II) infusion or transverse aortic constriction (TAC) compared with control mice. Expression level of programmed cell death 4 (PDCD4), a main target of miR-21, was significantly decreased in Ang II infused mice and TAC mice compared with control mice. Expression levels of transcriptional activator protein 1 (AP-1) and transforming growth factor-β1 (TGF-β1), which were downstream targets of PDCD4, were increased in Ang II infused mice and TAC mice compared with control mice. In vitro, mirVana-miR-21-specific inhibitor attenuated Ang II-induced PDCD4 downregulation and contributed to subsequent deactivation of AP-1/TGF-β1 signaling pathway in neonatal rat cardiomyocytes. Thus, suppression of miR-21 prevents hypertrophic stimulation-induced cardiac remodeling by regulating PDCD4, AP-1, and TGF-β1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

The association between microRNA-21 and hypertension-induced cardiac remodeling

et al. 2020

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“…In 2017, Zhou et al 85 performed a miRNA profiling approach in myocardium samples from an inducible DCM mouse model carrying a human TTN mutation. The authors described the upregulation in the expression levels of cardiomyocyte-enriched miR-208b.…”

Section: Micrornas and Nonischemic Dilated Cardiomyopathymentioning

confidence: 99%

Emerging role of microRNAs in dilated cardiomyopathy: evidence regarding etiology

Calderón‐Domínguez

Belmonte

Quezada-Feijoó

et al. 2020

Translational Research

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Dilated cardiomyopathy (DCM) is a heart muscle disease characterized by ventricular dilation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease. This cardiac disorder is a major health problem due to its high prevalence, morbidity, and mortality. DCM is a complex disease with a common phenotype but heterogeneous pathological mechanisms. Early etiological diagnosis and prognosis stratification is crucial for the clinical management of the patient. Advances in imaging technology and genetic tests have provided useful tools for clinical practice. Nevertheless, the assessment of the disease remains challenging. Novel noninvasive indicators are still needed to assist in decisionmaking. microRNAs (miRNAs), a group of small noncoding RNAs, have been identified as key mediators of cell biology. They are found in a stable form in body fluids and their concentration is altered in response to stress. Previous research has suggested that the miRNA signature constitutes a novel source of noninvasive biomarkers for a wide array of cardiovascular diseases. Specifically, several studies have reported the potential role of miRNAs as clinical indicators among the etiologies of DCM. However, this field has not been reviewed in detail. Here, we summarize the evidence of intracellular and circulating miRNAs in DCM and their usefulness in the development of novel diagnostic, prognostic and therapeutic approaches, with a focus on DCM etiology. Although the findings are still

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“…Over-expression of miR-208b was also found in patients with DCM not related to TTNtv. When miR-208b was inhibited, mice did not develop a DCM phenotype suggesting that miR-208b plays a role in development of DCM possibly through transcriptional regulation of titin, although the exact mechanism for miR-208b has not been demonstrated [ 75 ].…”

Section: Titin Transcriptional Modifications Are Associated With Dmentioning

confidence: 99%

Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure

Tharp

Mestroni

Taylor

2020

JCM

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Titin is the largest human protein and an essential component of the cardiac sarcomere. With multiple immunoglobulin(Ig)-like domains that serve as molecular springs, titin contributes significantly to the passive tension, systolic function, and diastolic function of the heart. Mutations leading to early termination of titin are the most common genetic cause of dilated cardiomyopathy. Modifications of titin, which change protein length, and relative stiffness affect resting tension of the ventricle and are associated with acquired forms of heart failure. Transcriptional and post-translational changes that increase titin’s length and extensibility, making the sarcomere longer and softer, are associated with systolic dysfunction and left ventricular dilation. Modifications of titin that decrease its length and extensibility, making the sarcomere shorter and stiffer, are associated with diastolic dysfunction in animal models. There has been significant progress in understanding the mechanisms by which titin is modified. As molecular pathways that modify titin’s mechanical properties are elucidated, they represent therapeutic targets for treatment of both systolic and diastolic dysfunction. In this article, we review titin’s contribution to normal cardiac physiology, the pathophysiology of titin truncation variations leading to dilated cardiomyopathy, and transcriptional and post-translational modifications of titin. Emphasis is on how modification of titin can be utilized as a therapeutic target for treatment of heart failure.

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Inhibition of miR-208b improves cardiac function in titin-based dilated cardiomyopathy

Cited by 42 publications

References 35 publications

The association between microRNA-21 and hypertension-induced cardiac remodeling

The association between microRNA-21 and hypertension-induced cardiac remodeling

Emerging role of microRNAs in dilated cardiomyopathy: evidence regarding etiology

Modifications of Titin Contribute to the Progression of Cardiomyopathy and Represent a Therapeutic Target for Treatment of Heart Failure

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