Project 10

Immunmodulatory effects of potassium and salt in vascular damage

Background: Hypercholesterolemia, atherosclerosis and hypertension are commonly observed in patients with cardiovascular diseases and strongly associated with increased mortality. Atherosclerosis and hypertension are characterized by increased reactive oxygen species (ROS) production, affecting vascular smooth muscle cell (VSMC) migration and proliferation, and therefore play a pivotal role in their pathogenesis. In addition to promoting atherosclerosis, hypercholesterolemia has been shown to increase vascular reactivity and induces hypertension.  However the precise molecular mechanisms are still not fully understood. Most recently, evidence arose that the p38 MAP-kinase (MAPK), which is activated by angiotensin (Ang) II, ROS and proinflammatory cytokines, plays an important role in promoting vascular reactivity and vascular injury. In apoE knockout mice (apoE-/-), a model for atherosclerosis, we found evidence that vascular p38 MAPK in the kidney is activated by augmented ROS generation. Likewise, inhibition of p38 MAPK attenuates the increased renal pressor response to Ang II. Beside the classical renin-angiotensin system with its key effector molecule Ang II, there is growing evidence that Ang-(1-7), a heptapeptide which is generated by the cleavage of Ang II by the angiotensin converting enzyme 2, has an important impact on cardiovascular function as it is characterized as a physiological antagonist of Ang II. Ang-(1-7) activates its own receptor, the G-coupled MAS receptor. 

Previous work: Recently, the group of Rump and others have shown that sustained Mas receptor activation by Ang-(1-7) attenuates Ang II induced cardiac hypertrophy as well as renal pressor response and improves endothelial dysfunction in atherosclerosis by reducing ROS generation. Conversely, deletion of the Mas receptor results in increased blood pressures and ROS generation. Despite a large body of evidence describing beneficial effects of Mas receptor activation in cardiovascular diseases, little is known about the influence of Mas receptor signaling on atherosclerosis and vascular reactivity. Interestingly, preliminary results from our lab have shown that chronic Mas receptor stimulation attenuates the increased vascular reactivity in the kidney of apoE(-/-) mice by reducing ROS induced p38 MAPK activation. To determine whether Mas receptor activation can attenuate the progression of atherosclerosis and vascular injury, we have generated atherosclerotic double (apoE-/-/Mas-/-) mice.
Dr. Le´s group demonstrated that glutathione S-transferase-µ1 (Gstm1), a member of the superfamily of glutathione S-transferases, regulates p38 MAPK activation through its role in handling ROS.  Dr. Le and associates showed that reduced Gstm1 expression levels are associated with increased ROS levels and consecutively enhanced p38 MAPK activation, leading to increased VSMC migration and proliferation, which are crucial steps in the pathogenesis of atherosclerosis and hypertension. Of note, approximately 30-50% of humans are completely deficient of Gstm1 which is associated with increased risks of hypertension atherosclerosis and coronary artery disease. The exact mechanisms for the role of Gstm1 in the pathogenesis of atherosclerosis and vascular function are still not known.  Dr. Le’s laboratory has generated a Gstm1 knockout mouse line. In preliminary data, they have found that Gstm1 KO mice have a significantly higher baseline blood pressure than wild-type mice. To determine the effects of loss of Gstm1 on the susceptibility and severity of atherosclerosis, Dr. Le’s laboratory is generating double Gstm1-/-/Apoe-/- KO mice. Given synergy and complementary expertise of both laboratories in p38 MAPK mediated smooth muscle cell signaling and its impact on vascular function, we will determine the effect of vascular p38 MAPK activation in driving vascular reactivity and atherosclerosis in hypercholesterolemia. In order to examine these effects, we have generated atherosclerotic apoE(-/-) mice lacking p38 MAPK only in VSMCs by using the cre loxP technique. In addition to identifying downstream pathways of p38 MAPK involved in the pathogenesis of atherosclerosis and vascular injury, we will examine together with Dr. Le’s lab whether Gstm1 and Mas receptor activation can attenuate these effects in order to identify target molecules for new therapeutic strategies.  

Publications

Yang, G., Chu, P. L., Rump, L. C., Le, T. H., and Stegbauer, J. (2017) ACE2 and the
Homolog Collectrin in the Modulation of Nitric Oxide and Oxidative Stress in Blood Pressure
Homeostasis and Vascular Injury. Antioxid Redox Signal doi: 10.1089/ars.2016.6950

Thieme, M., Sivritas, S. H., Mergia, E., Potthoff, S. A., Yang, G., Hering, L., Grave,
K.
, Hoch, H., Rump, L. C., and Stegbauer, J. (2017) Phosphodiesterase 5 inhibition
ameliorates angiotensin II-dependent hypertension and renal vascular dysfunction. Am J
Physiol Renal Physiol 312, F474-F481

Potthoff, S. A., Stamer, S., Grave, K., Konigshausen, E., Sivritas, S. H., Thieme, M.,
Mori, Y., Woznowski, M., Rump, L. C., and Stegbauer, J. (2016) Chronic p38 mitogenactivated
protein kinase inhibition improves vascular function and remodeling in angiotensin
II-dependent hypertension. J Renin Angiotensin Aldosterone Syst 12,17

Hammer, A., Yang, G., Friedrich, J., Kovacs, A., Lee, D. H., Grave, K., Jorg, S.,
Alenina, N., Grosch, J., Winkler, J., Gold, R., Bader, M., Manzel, A., Rump, L. C., Muller, D.
N., Linker, R. A., and Stegbauer, J. (2016) Role of the receptor Mas in macrophagemediated
inflammation in vivo. Proc Natl Acad Sci U S A 113, 14109-14114

Hoch, H., Hering, L., Crowley, S., Zhang, J., Yang, G., Rump, L. C., Vonend, O., and
Stegbauer, J. (2015) 9a.05: Sympathetic Nervous System Drives Renal Inflammation by
Alpha(2a)-Adrenoceptors. J Hypertens 33 Suppl 1, e118

 

Prof. Dr. med. Lars Christian Rump

Dept. of Internal Medicine / Nephrology

Johannes Stegbauer

Heinrich-Heine-Universität Dept. of Nephrology

Prof. Dr. Gorav Ailawadi

Thoracic and Cardiovascular Surgery Institute

Graduate Students

Mina Yakoub

Dept. of Internal Medicine / Nephrology
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