Syndecan-4 and integrin α11 involved in adverse cardiac remodelling

Andreas Romaine has identified two potential molecular targets for future heart failure therapies.


MAIN RESULTS:

  1. Integrin α11 is highly upregulated following aortic banding.

  2. Both syndecan-4 and integrin α11 are required to induce cardiac hypertrophic remodelling.
  3. A novel method of aortic banding results in cardiac hypertrophy with very low mortality.

THESIS DEFENCE:

Thesis: Proteoglycans and integrins as key regulators of cardiac remodelling in response to increased left ventricular afterload
Candidate: Andreas Romaine
Time: February 13, 2020 at 13:15
Place: Oslo University Hospital Ullevål, Kreftsenteret: Ground floor auditorium
Link to university website


SUMMARY:

(1) High levels of the cell surface mechanosensor integrin α11 leads to cardiac remodelling. Transgenic mice with high integrin α11 levels developed left ventricular hypertrophy and cardiac fibrosis within six months. Compared to wild type mice, intracellular hypertrophic signalling and secretion of soluble factors that increase collagen production in the heart were evident in the transgenic mice.

Moreover, the genetic expression of integrin α11 was markedly increased in cardiac cells from wild type mice following aortic banding.

(3) The proteoglycan syndecan-4, another cell surface mechanosensor, prevents degradation of osteopontin, which might protect the heart from adverse remodelling. Both osteopontin and syndecan-4 were upregulated in mice subjected to aortic banding. Syndecan-4 bound to osteopontin and protected it from being cleaved by thrombin. Thrombin-cleaved osteopontin induces cardiac fibrosis.

However, in the later phases of remodelling, syndecan-4 is shed and contributes to progression of cardiac fibrosis.

(4) Lack of integrin α11 and syndecan-4 protects against adverse remodelling following aortic banding. Following pressure overload in mice, both syndecan-4 and integrin α11 were required to induce cardiac hypertrophic remodelling.

(2) Romaine and co-workers also developed a novel model for increased mechanical strain on mice heart. By using o-rings with fixed inner diameter, the researches established a model of high precision aortic constriction, resulting in hypertrophy within one week and very low mortality.


REFERENCES:

(1) Romaine, A., Sørensen, I. W., Zeltz, C., Lu, N., Erusappan, P. M., Melleby, A. O., Zhang, L., Bendiksen, B., Robinson, E. L., Aronsen, J. M., Herum, K. M., Danielsen, H. E., Sjaastad, I., Christensen, G., & Gullberg, D. (2018). Overexpression of integrin α11 induces cardiac fibrosis in mice. Acta Physiologica222(2), e12932.

(2) Melleby, A. O., Romaine, A., Aronsen, J. M., Veras, I., Zhang, L., Sjaastad, I., Lunde, I. G., & Christensen, G. (2018). A novel method for high precision aortic constriction that allows for generation of specific cardiac phenotypes in mice. Cardiovascular research114(12), 1680-1690.

(3) Herum, K. M., Romaine, A., Wang, A., Melleby, A. O., Strand, M. E., Pacheco, J., Braathen, B., Dunér, P., Tønnessen, T., Lunde, I. G., Sjaastad, I., Brakebusch, C., McCulloch, A. D., Gomez, M. F., Carlson, C. R., & Christensen, G. (2020). Syndecan‐4 Protects the Heart From the Profibrotic Effects of Thrombin‐Cleaved Osteopontin. Journal of the American Heart Association9(3), e013518.