Mitogen-Activated Protein Kinases and Regulation of Mitochondrial Biogenesis in Human Cardiomyopathies
M Sebastiani, C Giordano, C Travaglini, E Perli, P Lilla Della Monica, F Musumeci, P Gallo, RW Taylor, G d'Amati. Sapienza Universit di Roma, Roma, Italy; Azienda Ospedalira S. Camillo-Forlanini, Roma, Italy; University of Newcastle, Newcastle-upon-Tyne, United Kingdom
Background: The most critical regulators of myocardial mitochondrial biogenesis are and its coactivator However, the upstream signaling pathways involved in PPARa/ PGC-1a complex activation are still unknown. The aim of our study was to evaluate the role of mitogen-activated protein kinases (MAPK) ERK1/2, JNK and p-38 in cardiac mitochondrial biogenesis.
Design: Activation of MAPK was detected by the Bioplex suspension array system on left ventricular samples from control hearts (n=2) and recipient explanted hearts with either a) mitochondrial cardiomyopathies (MIC) due to the m.4300A>G substitution in the mt-tRNAIle gene (n=3) or b) heart failure resulting from other aetiologies (n = 5). PGC1a gene expression was evaluated in the same samples by real-time PCR.
Results: In MIC hearts, we show marked mitochondrial proliferation and significant increase in the expression of PGC1a (15-fold as compared to controls); these were associated with increased phosphorylation of p-38 and JNK, but not of ERK1/2. In contrast, PGC1a was down-regulated in failing hearts due to other aetiologies whilst ERK1/2, along with p-38 and JNK were strongly activated.
Conclusions: We show that MIC hearts are characterized by a specific pattern of MAPK phosphorylation. Besides the well known effect of p38 on PGC1a induction, inhibition of ERK1/2 seems necessary for mitochondrial biogenesis in heart.
Tuesday, March 10, 2009 11:15 AM
Platform Session: Section H2, Tuesday Morning