TNF-α-mediated down-regulation of mitochondrial transcription factors: Rescue by Angiotensin-(1-7) peptide.

Manifesting initially as a physiological adaptation to pressure/volume overload, cardiac hypertrophy helps to maintain normal cardiac output via optimal mitochondrial function. However, chronic hypertension leads to pathological cardiac hypertrophy that is characterized by compromised cardiac output and mitochondrial dysfunction. Against this backdrop, we sought to delineate the molecular mechanisms underlying the regulation of mitochondrial transcription factors (mTFs; viz. Tfam, Tfb1m and Tfb2m which play a pivotal role in maintaining mitochondrial homeostasis) in cardiomyocytes. We show that the expression of mtTFs is repressed in the left ventricle of spontaneously hypertensive rats (SHR) as compared to normotensive Wistar Kyoto rats (WKY). In line with these findings, TNF-ɑ diminished the expression of mtTFs in H9c2 cardiomyoblasts. Ang-(1-7), an anti-inflammatory and anti-hypertensive peptide, reversed these effects of TNF-ɑ in vitro. We show that PGC-1ɑ-YY1 transcriptional complex acts as a molecular switch to modulate the expression of mtTFs. While TNF-ɑ prevents the formation of PGC-1ɑ-YY1 complex and promotes transcriptional repression of mtTFs mediated by YY1, Ang-(1-7) restores the complex formation, causing transcriptional activation of mtTFs. Thus, Ang-(1-7) emerges as an important regulator of cardiac mitochondrial biogenesis under inflammatory conditions.

Duke Scholars

Author Christopher Dale Kontos Medicine, Cardiology