Premium
Sirtuins as negative regulators of cardiac fibrosis
Author(s) -
Samant Sadhana,
Bindu Samik,
Ghorpade Prabhakar,
Pillai Vinodkumar,
Gupta Mahesh
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.674.5
Subject(s) - sirtuin , sirt3 , fibrosis , myofibroblast , sirt6 , biology , microbiology and biotechnology , endocrinology , cancer research , medicine , nad+ kinase , biochemistry , enzyme
Background and Objective Fibrosis results from a process where quiescent resident fibroblasts in a healthy tissue get transformed into myofibroblasts (myoFB). In the US an estimated 45% deaths per year are attributed to fibrotic diseases. Tissue fibrosis is considered one of the causative factors of the aging process and organ dysfunction. Sirtuins, the NAD+‐dependent deacetylases are shown to impact lifespan of organisms. Among the seven sirtuin isoforms expressed in mammalian cells, SIRT6 and SIRT3, which are localized in the nucleus and mitochondria, respectively, are shown to retard the aging‐associated diseases. We therefore set out to study their roles in development of tissue fibrosis. Methods and Results Fibroblasts isolated from human failing hearts showed increased expression of myoFB markers, including expression of α‐smooth muscle actin, fibronectin and collagen1 with concomitant decreased levels of SIRT6 and SIRT3. By immunoblotting and Masson‐trichrome staining we also observed up‐regulation of these myoFB markers in SIRT6(+/‐) and 12‐month old SIRT3(‐/‐) hearts, compared to age‐matched littermates,. These hearts also showed up‐regulation of TGF‐β1 and Smad3 levels. In experiments where SIRT3 or SIRT6 knocked‐down human cardiac fibroblasts were challenged with the pro‐fibrotic agonist angiotensin‐II, we observed significantly higher levels of TGF‐β1 and myoFB markers, compared to control fibroblasts. Over‐expression of these sirtuin isoforms reverted back the myoFB phenotype. Conclusion Though, SIRT6 and SIRT3 are localized in two different cellular compartments, both are capable of restraining TGF‐β signaling and blocking transformation of fibroblasts into myoFB. These sirtuins therefore can be considered candidates for designing anti‐fibrotic drugs. .