JOURNAL ARTICLE

Essential Role for Premature Senescence of Myofibroblasts in Myocardial Fibrosis

Kathleen Meyer, Bettina Hodwin, Deepak Ramanujam, Stefan Engelhardt, Antonio Sarikas
Journal of the American College of Cardiology 2016 May 3, 67 (17): 2018-28
27126529

BACKGROUND: Fibrosis is a hallmark of many myocardial pathologies and contributes to distorted organ architecture and function. Recent studies have identified premature senescence as a regulatory mechanism of tissue fibrosis, but its relevance in the heart remains to be established.

OBJECTIVES: This study investigated the role of premature senescence in myocardial fibrosis.

METHODS: Murine models of cardiac diseases and human heart biopsies were analyzed for characteristics of premature senescence and fibrosis. Loss-of-function and gain-of-function models of premature senescence were used to determine its pathophysiological role in myocardial fibrosis.

RESULTS: Senescence markers p21(CIP1/WAF1), senescence-associated ß-galactosidase (SA-ß-gal), and p16(INK4a) were increased 2-, 8-, and 20-fold (n = 5 to 7; p < 0.01), respectively, in perivascular fibrotic areas after transverse aortic constriction compared with sham-treated control subjects. Similar results were observed with cardiomyocyte-specific β1-adrenoceptor transgenic mice and human heart biopsies. Senescent cells were positive for platelet-derived growth factor receptor-α, vimentin, and α-smooth muscle actin, specifying myofibroblasts as the predominant cell population undergoing premature senescence in the heart. Inactivation of the premature senescence program by genetic ablation of p53 and p16(INK4a) (Trp53(-/-)Cdkn2a(-/-) mice) resulted in aggravated fibrosis after transverse aortic constriction, when compared with wild-type control subjects (49 ± 4.9% vs. 33 ± 2.7%; p < 0.01), and was associated with impaired cardiac function. Conversely, cardiac-specific expression of CCN1 (CYR61), a potent inducer of premature senescence, by adeno-associated virus serotype 9 gene transfer, resulted in ∼50% reduction of perivascular fibrosis after transverse aortic constriction, when compared with mock- or dominant-negative CCN1-infected control subjects, and improved cardiac function.

CONCLUSIONS: Our data establish premature senescence of myofibroblasts as an essential antifibrotic mechanism and potential therapeutic target in myocardial fibrosis.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
27126529
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"