Center for Molecular Medicine Cologne

Stephan Rosenkranz - assoc. RG 19

Role of Class I PI 3-kinase Isoforms in Vascular Diseases

Abstract

Vascular diseases including atherosclerosis, pulmonary hypertension (PH), or aortic aneurysm are characterized by vascular remodelling, inflammation, endothelial dysfunction and/or impaired vessel wall integrity. The goal is to discover pathogenic as well as protective signaling pathways and thus identify novel therapeutic strategies.

We focus on class I PI 3-kinase isoforms, playing significant roles downstream of cell surface receptors in health and disease. Class I PI 3-kinase isoforms comprise a regulatory and one of four catalytic subunits (p110a, p110b, p110d, and p110g), respectively. We showed that activation of p110a in smooth muscle cells (SMCs) is essential for pathogenic vascular remodelling in restenosis as well as in PH.

Whereas p110a emerges as a disease promoting enzyme and thus a promising therapeutic target, recent projects unravel critical physiological functions of p110 isoforms in the vasculature. Genetic inactivation of p110g worsens PH suggesting a rather protective role of this isoform. Exploring p110d in atherosclerotic mice, we unexpectedly found that lack of p110d in leukocytes led to enhanced plaque growth.

This effect was completely rescued by injection of wild type Treg indicating important atheroprotective functions of p110d in Treg. A recent project focuses on the physiological role of p110a in the aortic wall. Preliminary data suggest that p110a signalling maintains vascular integrity, while p110a deficiency in SMCs promotes aortic aneurysm formation. In conclusion, these data emphasize p110 isoforms as critical mediators of both protective and pathogenic processes in vascular diseases.

Clinical and Medical Relevance

Despite recent improvements, the morbidity and the mortality due to vascular diseases, remain unacceptably high.

Particularly, atherosclerosis is the underlying cause of about 50% of all deaths in westernized societies. There are currently still no pharmacological strategies to causally treat vascular dysfunction. PI 3-kinase isoforms are expressed in all relevant cell types including SMCs, endothelial cells and leukocytes, where they induce significant protective as well as pathogenic signaling pathways.

Elucidating these pathways in detail will provide promising new pharmacological targets.

Project Related Publications

  1. Rosenkranz, S., Howard, L.S., Gomberg-Maitland, M., Hoeper, M.M. (2020). Systemic consequences of pulmonary hypertension and right-sided heart failure. Circulation, epub ahead of print.
  2. Canepa M., Franssen, F.M.E., Olschewski, H., Lainscak, M., Böhm, M., Tavazzi, L., Rosenkranz S. (2019). Diagnostic and Therapeutic Gaps in Patients With Heart Failure and Chronic Obstructive Pulmonary Disease. JACC Heart Fail 10, 823-833.
  3. Klinke, A., Berghausen, E.M., Friedrichs, K., Molz, S., Lau, D., Remane, L., Berlin, M., Kaltwasser, C., Adam, M., Mehrkens, D., Mollenhauer, M., Manchanda, K., Ravekes, T., Heresi, G., Aytekin, M., Dweik, R., Hennigs, J., Kubala, L., Michaelsson, E., Rosenkranz, S., Rudolph, T.K., Hazen, S.L., Klose, H., Schermuly, R.T., Rudolph, V., Baldus, S. (2018). Myeloperoxidase aggravates pulmonary arterial hypertension by activation of vascular Rho-kinase. JCI Insight 3, e97530.
  4. Gerhardt, M.J., Marsh, J., Morrison, M., Kazlauskas, A., Khadka, A., Rosenkranz, S., De Angelis MM, Saint-Geniez M, Jacobo SMP. (2017). ER stress-induced aggresome trafficking of HtrA1 protects against proteotoxicity. J Mol Cell Biol 9, 516-532.
  5. Opitz, C.F., Hoeper, M.M., Gibbs, J.S.R., Kaemmerer, H., Pepke-Zaba, J., Coghlan, J.G., Scelsi, L., D’Alto, M., Olsson, K.M., Ulrich, S., Scholtz, W., Schulz, U., Grünig, E., Vizza, C.D., Staehler, G., Bruch, L., Huscher, D., Pittrow, D., Rosenkranz, S. (2016). Pre-capillary, combined, and post-capillary pulmonary hypertension: A pathophysiological continuum. J Am Coll Cardiol 68, 368-378.
  6. Rosenkranz, S., Gibbs, J.S.R., Wachter, R., De Marco, T., Vonk-Noordegraaf, A., Vachiéry J.L. (2016). Left ventricular heart failure and pulmonary hypertension. Eur Heart J 37, 942-954.
  7. Vantler, M., Jesus, J., Leppänen, O., Scherner, M., Berghausen, E.M., Mustafov, L., Chen, X., Kramer, T., Zierden, M., Gerhardt, F., ten Freyhaus, H., Blaschke, F., Sterner-Kock, A., Baldus, S., Zhao J.J., Rosenkranz, S. (2015). Class IA PI3K isoform p110a mediates vascular remodeling. Arterioscler Thromb Vasc Biol 35, 1434-1444.
  8. Ten Freyhas, H., Berghausen, E.M., Janssen, W., Leuchs, M., Zierden, M., Murmann, K., Klinke, A., Vantler, M., Caglayan, E., Kramer, T., Baldus, S., Schermuly, R.T., Tallquist, M.D., Rosenkranz, S. (2015). Genetic ablation of PDGF-dependent signaling pathways abolishes vascular remodeling and experimental pulmonary hypertension. Arterioscler Thromb Vasc Biol  35, 1236-1245.
Prof. Dr. Stephan Rosenkranz CMMC Cologne
Prof. Dr. Stephan Rosenkranz

Dept. III of Internal Medicine / RG location - CMMC Building

CMMC - assoc. Research Group

 

+49 221 478 32401

+49 221 478 97902

Dept. III of Internal Medicine / RG location - CMMC Building

CMMC Research Building University of Cologne Robert-Koch-Str. 21

50931 Cologne

http://herzzentrum.uk-koeln.de/de/kardiologie/forschung/ag_rosenkranz

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Publications - Stephan Rosenkranz

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