Abstract 3700: Proteomic Profiling of Chronic Pulmonary Hypertension Suggests Development of Both Adaptive and Maladaptive Pathology
Background. The molecular mechanisms governing right atrial (RA) and ventricular (RV) hypertrophy and failure in chronic pulmonary hypertension (CPH) remain unclear. The purpose of this investigation was to characterize RA and RV protein changes in CPH and determine their adaptive versus maladaptive role on hypertrophic development.
Methods. Nine dogs underwent sternotomy and RA injection with 3 mg/kg dehydromonocrotaline (DMCT) to induce CPH (n=5) or sternotomy without DMCT (n=4). At 8 –10 weeks (34% rise in RV pressure with DMCT, p<0.05), RA and RV proteomic analyses were completed after trypsinization of cut 2D-gel electrophoresis spots and peptide sequencing using high-resolution nano-LC-mass spectrometry/database searching.
Results. In the RV, 13 protein spots were significantly altered with CPH compared to sham (confidence filters: 99% minimum protein, 2 peptides, 95% minimum peptide). Downregulated RV proteins included
contractile elements: troponin T & C (−1.6 fold change), myosin light polypeptide (−1.5), myosin regulatory light chain 2 (−1.9),
cellular energetics modifier: fatty-acid binding protein (−1.5), and
ROS scavenger: superoxide dismutase 1 (−1.7).
Conversely, beta-myosin heavy chain was upregulated (+1.7 fold change). In the RA, 22 proteins spots were altered including the following downregulated proteins
contractile elements: tropomyosin 1 alpha chain (−1.9 fold change),
cellular energetic proteins: ATP synthase (−1.5), fatty-acid binding protein (−2.5), and
ubiquitination: polyubiquitin (−3.5). Crystallin alpha B (inhibitor of hypertrophy) was upregulated in both the RV (+2.2 fold change) and RA (+2.6).
Conclusions. In early stage hypertrophy there is adaptive upregulation of major RA and RV contractile substituents and attenuation of the hypertrophic response. However, there are multiple indices of maladaptive pathology including considerable cellular stress associated with aberrancy of actin machinery activity, decreased efficiency of energy utilization, and potentially decreased protein quality control.