Clin Res Cardiol 101, Suppl 1, April 2012

P991 - Altered Stat3 signaling in beta-parvin knockout mice results in pathological cardiac adaptations towards physiological loading
F. Suhr1, I. Thievessen2, K. Brixius1, O. Dewald3, B. Fleischmann4, R. Fässler5, W. Bloch1
1Abt. für Molekulare und Zelluläre Sportmedizin, Deutsche Sporthochschule Köln, Köln; 2Abteilung für Molekulare Medizin, MPI für Biochemie, München; 3Klinik und Poliklinik für Herzchirurgie, Universitätsklinikum Bonn, Bonn; 4Physiologisches Institut, Universitätsklinikum Bonn, Bonn; 5Abteilung für Molekulare Medizin, Max-Plank-Institut für Biochemie, München;
Background: Mechanical forces mediate physiological and pathological cardiac hypertrophy. This adaptation depends on focal adhesions that are recruited to the integrin cytoplasmic domains. A central focal adhesion structure is a complex constituted by integrin-linked kinase (Ilk), PINCH and the F-actin binding protein parvin, also described as IPP complex. Capillaries are crucially involved in cardiac muscle regulation. Disturbed capillary adaptations towards physiological loading, such as exercise, result in maladaptive cardiac phenotypes. Signal transducer and activator of transcription (Stat)-3 is a potent regulator of capillarization. Upon phosphorylation at Y705 Stat3 translocates into the nucleus to promote angiogenic genes, including VEGF. Dephosphorylation of Stat3 at Y705 therefore mediates reduced capillarization and thus seems to be likely to play crucial roles in cardiac phenotypes.
Hypothesis Ilk-/- results in negative adaptations of the heart and due to their close association it was hypothesized that also Parvb-/- leads to pathological cardiac adaptations either during development, during adultness or during chronic mechanical stimulation in adult animals. Additionally, it was demonstrated recently that Parvb is involved in Stat3 regulation. The aim of the present study therefore was to investigate effects of a constitutive Parvb gene deletion (Parvb-/-) on cardiac adaptation.
Methods: Parvb cDNA-containing fragment of EST-clone #2999-a09 (Image: 1193744, GenBank: AA726210) was used to screen a 129/sv mouse P1 artificial chromosome library. 3 homologous recombinant ES cell clones were injected into C57BL/6J blastocysts and chimeric males were bread to C57BL/6J females to generate Parvb+/- mice. Transverse aortic constriction (TAC) model was performed control and Parvb-/- mice. High resolution mouse echocardiography was performed using a commercial ultrasound system. Experiments were performed with control and Parvb-/- mice. Chronic treadmill exercise was performed over a period of 4 wks. Acute treadmill exercise consisted of a single 15 min exercise bout at 18 m*min-1, angle of 10°. 8 µm sections were cut to investigate capillarization histologically. WB was used to quantify total Stat3 and phosphorylated Stat3Tyr705 in control, acute exercised and TAC hearts.
Results: No cardiac phenotype in Parvb-/- animals under resting conditions was observed. Chronic mechanical stimulation resulted in decreased capillarization in Parvb-/- cardiomyocytes. Therefore, acute exercise was used to investigate Stat3 phosphorylation patterns. It was observed that acute exercise leads to decreased Stat3Y705 phosphorylation in Parvb-/- hearts compared to WT controls. Capillarization was higher in WT TAC and Parvb-/- TAC conditions compared to controls. However, no differences in capillarization between WT TAC and Parvb-/- TAC conditions were. Corresponding to this observation also the Stat3Y705 pattern did not significantly differ between WT TAC and Parvb-/- TAC hearts, but was higher compared to control conditions.
Conclusion: These data support the hypothesis that Parvb-/- plays a central role in cardiac adaptations towards physiological loading, as induced by exercise. The maladaptive adaptation towards physiological loading of the heart seems to be dependent on altered Stat3 phosphorylation at Y705 in Parvb-/- hearts. In conclusion, Parvb-/- plays a central role for cardiac adaptations towards physiological, but not pathological, loading.
Clin Res Cardiol 101, Suppl 1, April 2012
Zitierung mit Vortrags- oder Posternummer s.o.
DOI 10.1007/s00392-012-1100-6