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COmpound 21 and MElatonin in CArdiovascular REmodeling

Final Report Summary - COME-IN-CARE (COmpound 21 and MElatonin in CArdiovascular REmodeling)

Cardiovascular (CV) diseases are the major source of morbidity and mortality in the EU. However, the control of hypertension, the most prevalent modifiable CV risk factor, still remains insufficient. Many current therapies reduce the unfavourable stimulation of angiotensin type 1 receptors. Some benefits of such blocked were recently attributed to enhanced activation of type 2 receptor (AT2R). Only the recent discovery of a suitable AT2R agonist, compound 21, allowed a direct investigation of long-term AT2R activation in hypertension and CV remodelling. The pineal hormone melatonin was also suggested to prevent of fibrosis and to be suitable for the use in combination with a renin-angiotensin system modulating drug. Our project aimed to investigate the effects of compound 21 and melatonin on blood pressure and cardiovascular remodeling in the L-NAME hypertension.

Hypertension was induced by administration of NO-synthase inhibitor, L-NAME, in rats, which were concomitantly treated with compound 21, melatonin and their combination. The left ventricular (LV) function was determined by echocardiography and catheterisation, which was also used to determine pulse wave velocity (PWV), an important independent CV risk factor. Fibrosis was evaluated by hydroxyproline concentration and histomorphology, RNA expression of selected genes was determined by polymerase chain reaction (PCR). Melatonin improved LV systolic and diastolic function and compound 21 prevented the increase of PWV in L-NAME rats. Both substances exerted anti-inflammatory and anti-fibrotic effects despite achieving only non-significant blood pressure or NO production modulation.

Thus, both melatonin and compound 21 displayed potential for CV risk reduction independently of blood pressure decrease. Hypertensive and CV patients would benefit from prevention of fibrosis or PWV augmentation. However, patients and conditions need to be identified, in which such an intervention would be most beneficial. Our results suggest that the stimulation of AT2R might be especially beneficial in conditions involving inflammatory mechanisms and in conditions were blood pressure reduction is not required or even undesired.

The scientific results were published in three original CC publications (J. Hypertens, 2009; J. Pineal Res, 2010; J. Hypertens, 2010) with one more in preparation; and were presented on 11 international conferences. In addition, two review CC manuscripts (Nature Rev Cardiol, J. Hypertens), related to the topic, were published. The ECs contribution and project summary were published at the fellow's web-site (please see online), the host's web page (please see online) and host's report (please see online).

The realisation of the project provided the fellow with a superior training opportunity. He acquired and improved experimental skills (blood pressure measurement, catheterisation, echocardiography, histological methods and novel RT-PCR analysis formula), presentation skills (by participation on institute seminaries and international conferences) and writing skills and the gain of knowledge (preparation of two review articles). He also extended his collaborative network, experienced public-private partnership and cooperation and further developed his leadership and teaching skills (supervision of doctorate thesis, participation in teaching at host institute).

To summarise, the COME-IN-CARE project yielded important scientific results, suggesting novel means for CV risk reduction; boosted the fellow's publication output; provided him superior training and collaborative opportunity and substantially helped the fellow on his path to become an independent researcher. As such it did not only support the scientific progress but also the human potential in the EU as a prerequisite for the promotion of knowledge-based economy.