MicroRNA profiling of the feline left heart identifies chamber-specific expression signatures in health and in advanced hypertrophic cardiomyopathy

Joshua, Jessica; Caswell, Jeff; Rodríguez, Josep M. Monné; Kipar, Anja; O’Sullivan, Lynne; Wood, Geoffrey A.; Fonfara, Sonja

doi:10.1016/j.jmccpl.2023.100037

Cited by 4 publications

(1 citation statement)

References 104 publications

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“…This is in contrast to observations of Roman et al, who described antihypertrophic effects of transgenic miR-181c/d deletion in a murine model of obesity ( 24 ). We expect that differences in timing of miR-181c modulation, incomplete suppression of miR-181c by antagomiR, or supplementary effects of miR-181d might have led to this discrepancy ( 38 ).…”

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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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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Evaluation of potential novel biomarkers for feline hypertrophic cardiomyopathy

Chong,

Joshua,

Raheb

et al. 2024

Research in Veterinary Science

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Feline hypertrophic cardiomyopathy: Does the microRNA‐mRNA regulatory network contribute to heart sarcomeric protein remodelling?

Guelfi,

Venanzi,

Capaccia

et al. 2024

Int J Experimental Path

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Feline primary hypertrophic cardiomyopathy (HCM) is an intrinsic myocardial disease characterized by concentric hypertrophy of the left ventricle. In the present study, we investigated the microRNA‐mRNA regulatory network in feline myocardial tissue affected by primary (HCMI) and secondary HCM (HCMII). MRNA expression levels of sarcomeric genes, including, TNNT2, TNNI3, MYH7, MYBPC3, TPM1 and ACTC1 were assessed in the FFPE myocardial tissues. FFPE tissues from healthy cats were sequenced by the NGS, to explore, in the entire non‐deposited miRNome, the expression level of microRNAs targeting the complementary sequences of selected sarcomeric mRNAs. The sarcomeric genes TNNT2, MYH7, MYBPC3 and TPM1 showed a statistically significant upregulation in HCMI compared to HCMII (p < .01), except ACTC1 which was downregulated (p < .01); TNNI3 showed no statistically significant difference. In HCMII miR‐122‐5p, miR‐338‐3p, miR‐484, miR‐370‐3p, miR‐92b‐3p, miR‐375 and miR‐370‐3p showed a significant upregulation (p < .01) compared to control. The exception was miR‐30a‐5p which showed downregulation. Worthy of note is the 4‐fold higher expression of miR‐370‐3p, a key regulator of MYBPC3, in HMCI compared to HMCII. This research does not solve the aetiological mystery of HCM, but it may help to find a way to help diagnose and define the prognosis of HCM in cats.

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MicroRNA profiling of the feline left heart identifies chamber-specific expression signatures in health and in advanced hypertrophic cardiomyopathy

Cited by 4 publications

References 104 publications

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

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

Evaluation of potential novel biomarkers for feline hypertrophic cardiomyopathy

Feline hypertrophic cardiomyopathy: Does the microRNA‐mRNA regulatory network contribute to heart sarcomeric protein remodelling?

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