Project Details
Projekt
STSTAT3 regulates via microRNAs and the ubiquitin proteasomal system the homeostasis of sarcomeric myosin heavy chain proteins and impacts thereby on cardiac hypertrophy and atrophyAT3, a potential key regulator of sarcomeric myosin heavy chain proteins in the heart
Subject Area
Cardiology, Angiology
Term
from 2014 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 252619239
Cachexia is a potent predictor of morbidity and mortality in patients with heart failure and advanced cancer. Pathological mechanisms in cachectic conditions in both disease types may include inflammation and peripheral organ dysfunction, which correlate with disease severity and clinical outcome and lead to cardiac atrophy. Reduced contractile function in patients with heart failure is in part caused by a decrease in myosin heavy chain (MHC) protein content and functionality. We observed that in dilated cardiomyopathy (DCM) and in peripartum cardiomyopathy (PPCM), characterized by low STAT3 expression, increased expression of microRNA-199a-5p (miR-199a) is present. Upregulation of miRNA-199a impairs the transcription of a- and bMHC in cardiomyocytes leading to decreased MHC levels associated with a loss in sarcomere organization. The decrease in a- and bMHC transcription is caused by a miR-199a-mediated suppression of the ubiquitin conjugating enzymes (Ube)2i, 2g1 and 2o. Consistent with a link between STAT3, miR-199a and the Ube2o enzyme, mice that lack gp130-mediated STAT3 activation after myocardial infarction (MI) lack post MI induced upregulation of Ube2o and display lower total cardiac MHC content. We observed that not only low STAT3 expression but also continuous high activation of STAT3 affects cardiac a- and bMHC expression but mainly at the posttranscriptional level. Such a situation is present in mice with cardiac atrophy due to colon-26 adenoma or B16-F10 melanoma tumors. In mice with B16-F10 the high and continuous activation of STAT3 is associated with reduced cardiac function and a decrease in a- and bMHC protein content, while other sarcomeric proteins such as Troponin T or Tropomyosin are not affected. We found that miR-199a is reduced in hearts of these tumor mice. Proteomics revealed that antagomir-mediated reduction of normal miR-199a expression in cardiomyocytes promotes enhanced ubiquitin proteosomal system (UPS)-mediated degradation of a- and bMHC. These features may be specific for tumor types that induce high STAT3 activation in the heart, since mice with a hepatoma tumor show neither STAT3 activation, nor cardiac atrophy or loss of cardiac MHC protein. We hypothesize that conditions that impair the regulation of STAT3 in cardiomyocytes in both directions, either too low or too high, evoke pathophysiological alterations in sarcomeric MHC proteins in cardiomyocytes. These STAT3 related mechanisms seem to affect functionality and turnover of cardiac MHC proteins and may thereby impact on cardiomyocyte function, geometry and survival. In the present project, we aim to understand the underlying molecular mechanisms that link STAT3 signaling to modulations of a- and bMHC proteins after MI, in DCM and in PPCM and in tumor induced cardiac atrophy. In parallel, we will investigate if molecules involved in these circuits may be suitable novel therapeutic targets in the cardiac disease types mentioned above.
DFG Programme
Research Grants
