miR-181c targets Parkin and SMAD7 in human cardiac fibroblasts: Validation of differential microRNA expression in patients with diabetes and heart failure with preserved ejection fraction

Jankauskas, Stanislovas S.; Mone, Pasquale; Avvisato, Roberta; Varzideh, Fahimeh; Gennaro, Stefano De; Salemme, Luigi; Macina, Gaetano; Kansakar, Urna; Cioppa, Angelo; Frullone, Salvatore; Gambardella, Jessica; Mauro, Marco Di; Tesorio, Tullio; Santulli, Gaetano

doi:10.1016/j.mad.2023.111818

Cited by 18 publications

(13 citation statements)

References 78 publications

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“…50–52 Smad7 mRNA can also be regulated at the posttranscriptional level by some miRNAs. 53,54 These aforementioned observations suggest that regulating Smad7 mRNA appears to be a major approach to control intracellular Smad7. Here, we unveiled that EGT upregulates Smad7 at the mRNA level in LX-2 HSCs.…”

Section: Discussionmentioning

confidence: 99%

Ergothioneine suppresses hepatic stellate cell activation via promoting Foxa3-dependent potentiation of the Hint1/Smad7 cascade and improves CCl₄-induced liver fibrosis in mice

Shu,

Lei,

et al. 2023

Food Funct.

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Section: Discussionmentioning

confidence: 99%

Ergothioneine suppresses hepatic stellate cell activation via promoting Foxa3-dependent potentiation of the Hint1/Smad7 cascade and improves CCl₄-induced liver fibrosis in mice

Shu,

Lei,

et al. 2023

Food Funct.

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“…A few studies have already proven the clinical value of miR-181c-5p: increased levels of circulating miR-181c-5p were detected in aged HFpEF patients with diabetes ( 29 ) and in HFpEF patients with a low response for exercise training ( 30 ). Recent in vitro studies in human cardiac fibroblasts identified SMAD7 as a new cardiac target of miR-181c-5p, which suggests a potential role for miR-181c-5p in cardiac fibrosis ( 29 ). In this study we now confirm in vivo an effect of miR-181c-5p on cardiac fibrosis through the TGF-β axis.…”

Section: Discussionmentioning

confidence: 99%

Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failure model

Boen,

Gevaert,

Dendooven

et al. 2024

Front. Cardiovasc. Med.

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AimsMiR-181c-5p overexpression associates with heart failure (HF) and cardiac damage, but the underlying pathophysiology remains unclear. This study investigated the effect of miR-181c-5p inhibition on cardiac function and fibrosis in a rodent model of diastolic dysfunction, and evaluated additional effects on kidney as relevant comorbid organ.Methods and resultsDiastolic dysfunction was induced in male C57/BL6J mice (n = 20) by combining high-fat diet, L-NG-nitroarginine methyl ester, and angiotensin II administration, and was compared to sham controls (n = 18). Mice were randomized to subcutaneous miR-181c-5p antagomiR (INH) or scrambled antagomiR injections (40 mg/kg/week). HF mice demonstrated diastolic dysfunction and increased fibrosis, which was attenuated by INH treatment. Remarkably, HF + INH animals had a threefold higher mortality rate (60%) compared to HF controls (20%). Histological examination revealed increased glomerular damage in all INH treated mice, and signs of thrombotic microangiopathy (TMA) in mice who died prematurely. Quantitative polymerase chain reaction demonstrated a miR-181c-5p-related downregulation of cardiac but not renal Tgfbr1 in HF + INH mice, while INH treatment reduced renal but not cardiac Vegfa expression in all mice.ConclusionThis study demonstrates cardiac anti-fibrotic effects of miR-181c-5p inhibition in a rodent HF model through targeting of Tgfbr1 in the heart. Despite improved diastolic function, HF + INH mice had higher mortality due to increased predisposition for TMA, increased renal fibrosis and glomerular damage, associated with Vegfa downregulation in kidneys.

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“…Another prevailing theory is that obesity-associated HFpEF is driven by a comorbidity-induced systemic proinflammatory state [ 39 – 41 ]. For example, the microRNA miR-181c is differentially expressed in patients with diabetes and comorbid HFpEF, and overexpression of miR-181c has been associated with proinflammatory conditions [ 42 ]. Similarly, testosterone has demonstrated anti-inflammatory effects [ 43 ], and testosterone deficiency has been associated with HFpEF in males with a cardio-metabolic profile [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Obesity and metabolic syndrome in patients with heart failure with preserved ejection fraction: a cross-sectional analysis of the Veradigm Cardiology Registry

Bae,

Kallenbach,

Nelson

et al. 2024

BMC Endocr Disord

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Background The proportion of heart failure patients with preserved ejection fraction has been rising over the past decades and has coincided with increases in the prevalence of obesity and metabolic syndrome. The relationship between these interconnected comorbidities and heart failure with preserved ejection fraction (HFpEF) is still poorly understood. This study characterized obesity and metabolic syndrome among real-world patients with HFpEF. Methods We identified adults with heart failure in the Veradigm Cardiology Registry, previously the PINNACLE Registry, with a left ventricular ejection fraction measurement ≥ 50% between 01/01/2016 and 12/31/2019. Patients were stratified by obesity diagnosis and presence of metabolic syndrome (≥ 3 of the following: diabetes, hypertension, hyperlipidemia, and obesity). We captured baseline demographic and clinical characteristics and used multivariable logistic regression to examine the odds of having cardiac (atrial fibrillation, coronary artery disease, coronary artery bypass surgery, myocardial infarction, and stroke/transient ischemic attack) and non-cardiac (chronic kidney disease, chronic liver disease, and peripheral artery disease) comorbidities of interest. The models adjusted for age and sex, and the main covariates of interest were obesity and metabolic burden score (0–3 based on the presence of diabetes, hypertension, and hyperlipidemia). The models were run with and without an obesity*metabolic burden score interaction term. Results This study included 264,571 patients with HFpEF, of whom 55.7% had obesity, 52.5% had metabolic syndrome, 42.5% had both, and 34.3% had neither. After adjusting for age, sex, and burden of other metabolic syndrome-associated diagnoses, patients with HFpEF with obesity had lower odds of a diagnosis of other evaluated comorbidities relative to patients without obesity. The presence of metabolic syndrome in HFpEF appears to increase comorbidity burden as each additional metabolic syndrome-associated diagnosis was associated with higher odds of assessed comorbidities except atrial fibrillation. Conclusion Obesity was common among patients with HFpEF and not always co-occurring with metabolic syndrome. Multivariable analysis suggested that patients with obesity may develop HFpEF in the absence of other driving factors such as cardiovascular disease or metabolic syndrome.

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miR-181c targets Parkin and SMAD7 in human cardiac fibroblasts: Validation of differential microRNA expression in patients with diabetes and heart failure with preserved ejection fraction

Cited by 18 publications

References 78 publications

Ergothioneine suppresses hepatic stellate cell activation via promoting Foxa3-dependent potentiation of the Hint1/Smad7 cascade and improves CCl₄-induced liver fibrosis in mice

Ergothioneine suppresses hepatic stellate cell activation via promoting Foxa3-dependent potentiation of the Hint1/Smad7 cascade and improves CCl₄-induced liver fibrosis in mice

Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failure model

Obesity and metabolic syndrome in patients with heart failure with preserved ejection fraction: a cross-sectional analysis of the Veradigm Cardiology Registry

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miR-181c targets Parkin and SMAD7 in human cardiac fibroblasts: Validation of differential microRNA expression in patients with diabetes and heart failure with preserved ejection fraction

Cited by 18 publications

References 78 publications

Ergothioneine suppresses hepatic stellate cell activation via promoting Foxa3-dependent potentiation of the Hint1/Smad7 cascade and improves CCl4-induced liver fibrosis in mice

Ergothioneine suppresses hepatic stellate cell activation via promoting Foxa3-dependent potentiation of the Hint1/Smad7 cascade and improves CCl4-induced liver fibrosis in mice

Divergent cardiac and renal effects of miR-181c-5p inhibition in a rodent heart failure model

Obesity and metabolic syndrome in patients with heart failure with preserved ejection fraction: a cross-sectional analysis of the Veradigm Cardiology Registry

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Ergothioneine suppresses hepatic stellate cell activation via promoting Foxa3-dependent potentiation of the Hint1/Smad7 cascade and improves CCl₄-induced liver fibrosis in mice

Ergothioneine suppresses hepatic stellate cell activation via promoting Foxa3-dependent potentiation of the Hint1/Smad7 cascade and improves CCl₄-induced liver fibrosis in mice