Bmi1 limits dilated cardiomyopathy and heart failure by inhibiting cardiac senescence.

I Gonzalez-Valdes,A Bujarrabal,J.A Enriquez,P Garcia-Pavia,J.M Redondo,A Hidalgo,L.J Jimenez-Borreguero,J.M Ruiz-Cabello,S Gonzalez,L Padron-Barthe,E Lara-Pezzi,I Hidalgo,J.L De La Pompa,Pablo Gómez-Del Arco

doi:10.1038/ncomms7473

Abstract

Dilated cardiomyopathy (DCM) is the most frequent cause of heart failure and the leading indication for heart transplantation. Here we show that epigenetic regulator and central transcriptional instructor in adult stem cells, Bmi1, protects against DCM by repressing cardiac senescence. Cardiac-specific Bmi1 deletion induces the development of DCM, which progresses to lung congestion and heart failure. In contrast, Bmi1 overexpression in the heart protects from hypertrophic stimuli. Transcriptome analysis of mouse and human DCM samples indicates that p16INK4a derepression, accompanied by a senescence-associated secretory phenotype (SASP), is linked to severely impaired ventricular dimensions and contractility. Genetic reduction of p16INK4a levels reverses the pathology of Bmi1-deficient hearts. In parabiosis assays, the paracrine senescence response underlying the DCM phenotype does not transmit to healthy mice. As senescence is implicated in tissue repair and the loss of regenerative potential in aging tissues, these findings suggest a source for cardiac rejuvenation.

Highlights

Dilated cardiomyopathy (DCM) is the most frequent cause of heart failure and the leading indication for heart transplantation
Representative views are shown of external anatomy and haematoxylin and eosin (H&E) staining on sections in adult hearts, Masson’s trichrome staining to detect fibrosis and left ventricular muscle sections stained with wheatgerm agglutinin (WGA; bottom row; bars, 10 mm). (e,f) Trans-thoracic M-mode echocardiographic and physiological analyses of Bmi1fl;NkxCre and Bmi1f/ mice
Representative views are shown of external anatomy and H&E staining on sections in adult hearts (12-week-old; top two rows; bars, 50 mm), Masson’s trichrome staining to detect fibrosis and left ventricular muscle sections stained with WGA to detect cardiomyocyte borders. (b) M-mode echocardiographic analysis of Bmi1fl;aMHCCre and Bmi1fl mice

Summary

Perls prusian

Representative views are shown of external anatomy (top row; bars, 0.5 cm) and haematoxylin and eosin (H&E) staining on sections in adult hearts (second row; bars, 1 mm), Masson’s trichrome staining to detect fibrosis (third row; bars, 40 mm) and left ventricular muscle sections stained with wheatgerm agglutinin (WGA; bottom row; bars, 10 mm). (e,f) Trans-thoracic M-mode echocardiographic and physiological analyses of Bmi1fl;NkxCre and Bmi1f/ mice. (e,f) Trans-thoracic M-mode echocardiographic and physiological analyses of Bmi1fl;NkxCre and Bmi1f/ mice. Panel i shows representative traces from Bmi1fl;NkxCre and Bmi1f/ mice at 7, 15 and 22 weeks of age. That Bmi[1] is critical to maintain adult heart function. To test whether heart failure was sensitive to the Bmi[1] dosage, To confirm the requirement of Bmi[1] in the adult heart, we we analysed the hearts of Bmifl/ þ ;aMHC-Cretg/ þ and Bmifl/ þ ; used a tamoxifen (TM)-inducible a-myosin heavy chain aMHC-Cre þ / þ mice. Young Bmi[1] heterozygotes showed no (aMHC)TM-Cre line[27] to delete Bmi[1] in the hearts of 5-weeknoticeable cardiac defects (Supplementary Fig. 2c); at old adult mice (Fig. 3a,b).

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Findings

Author contributions