Una aproximación translacional desde la clínica a la experimentación animal: Estudio del papel del eje CCL11/CCR3 y la inflamación eosinofílica en la patología cardiovascular asociada a desórdenes metabólicos


Cardiovascular disease (CVD) remains the leading cause of death worldwide and was responsible for nearly 18 million deaths in 2017 [1, 2]. Recognizing this situation, all World Health Organization member states have committed to provide counseling and drug treatments for at least 50% of people with a high risk of developing CVD by 2025 [1, 3]. CVD is a complex multifactorial disease, and many factors contribute significantly to disease development, but chief amongst these is atherosclerosis, which is considered as the cardinal underlying pathology [4].

Atherosclerosis is a chronic vascular disease that bears several histopathologic similarities to chronic inflammation triggering the accumulation of intermediates of cholesterol metabolism such as LDL and apolipoprotein B (apoB), and also different immune cells including macrophages and T lymphocytes in the walls of the arteries [5], leading to the eventual formation of an atheroma plaque. In turn, rupture of the atheroma plaque can lead to the formation of thrombi, which can occlude an artery and cause cardiovascular events such as myocardial infarction, stroke, or loss of function of the extremities [6, 7]. Mechanistic understanding of atherothrombosis is, however, unsatisfactory. The likelihood of developing atherosclerosis is also known to be enhanced by several risk factors such as hypertension, smoking, obesity, diabetes mellitus, and dysmetabolism [8, 9], and several studies have clearly demonstrated the interrelationship between low grade of systemic inflammation (LGSI) and several pathologies such as hypercholesterolemia or metabolic syndrome [10, 11]. In addition, one of the earliest stages of atherogenesis is endothelial dysfunction, a proinflammatory and prothrombotic phenotype of the endothelium [12] leading to the attachment and the subsequent migration of leukocytes.

On the other hand, abdominal aortic aneurysm (AAA) is a localized dilatation of the abdominal aorta and occurs most commonly in up to 9% of adults older than 65 years of age [13]. Currently, the clinical therapeutic approach to AAA is limited to surgical repair, and is not indicated in those patients with small AAA or asymptomatic. Pathological features of AAA include chronic vascular inflammation of the aortic wall, progressive degradation of extracellular matrix and increased neovascularization [14]. Because the high mortality rate associated with AAA it is important to identify new effective therapeutic strategies to prevent its progression.

Therefore, since inflammation has emerged as a crucial force driving the initiation and progression of atherosclerosis and AAA [13-20], a better understanding of the systemic inflammatory response that precedes or is involved in these processes as well as the role of different immune players, could help to establish novel therapeutic avenues that might inhibit or even prevent atherosclerosis and AAA development.


After years of collaboration in several independent projects on previous national an autonomic calls, the Inflammation group (PI: María Jesús Sanz) and the Cardiometabolic Risk and Diabetes group (PI: José T. Real and Sergio Martinez-Hervás), both from the Biomedical Research Institute INCLIVA and the University of Valencia, joined forces and obtained a grant in 2019 ‘Programa PROMETEO para grupos de investigación de Excelencia’ from Generalitat Valenciana’.

In this project the joined effort of basic and clinical researchers aims to elucidate novel immune players and mechanisms involved in the inflammatory status and endothelial dysfunction associated to different metabolic disorders (MD) as key tools in the detection of new CV risk biomarkers or targets for therapeutic intervention. For this purpose we have proposed a multidisciplinary approach that combines in vivo, in vitro and ex-vivo animal and human studies. The main goal is to improve our basic and clinical knowledge of the molecular and cellular mechanisms involved in the vascular inflammation caused by risk factors of atherosclerosis or AAA to provide the basis for a proper translational research and, a rapid application of our findings to the clinic. Nowadays, understanding immune system behavior (Immunome) is believed to become a crucial and powerful strategy for CVD prognosis and treatment outcome.

  1. Kaptoge S, P.L., De Bacquer D, World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. Lancet Glob Health, 2019. 7(10): p. e1332-e1345.
  2. Group, W.C.R.C.W., World Health Organization cardiovascular disease risk charts: revised models to estimate risk in 21 global regions. Lancet Glob Health, 2019. 7(10): p. e1332-e1345.
  3. Wang H., N.M., Allen C., Barber R., Bhutta Z., Carter A., et al., Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet, 2016. 388(10053): p. 1459-1544.
  4. Moore, K.J., Targeting inflammation in CVD: advances and challenges. Nat Rev Cardiol, 2019. 16(2): p. 74-75.
  5. Back, M., et al., Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol, 2019. 16(7): p. 389-406.
  6. Rahman, T., et al., Enhanced status of inflammation and endothelial activation in subjects with familial hypercholesterolaemia and their related unaffected family members: a case control study. Lipids Health Dis, 2017. 16(1): p. 81.
  7. Escate, R., et al., miR-505-3p controls chemokine receptor up-regulation in macrophages: role in familial hypercholesterolemia. Faseb j, 2018. 32(2): p. 601-612.
  8. Libby, P., et al., Inflammation, Immunity, and Infection in Atherothrombosis: JACC Review Topic of the Week. J Am Coll Cardiol, 2018. 72(17): p. 2071-2081.
  9. Wong, N.D., et al., Cardiovascular Risk Factor Targets and Cardiovascular Disease Event Risk in Diabetes: A Pooling Project of the Atherosclerosis Risk in Communities Study, Multi-Ethnic Study of Atherosclerosis, and Jackson Heart Study. Diabetes Care, 2016. 39(5): p. 668-76.
  10. Collado, A., et al., Novel Immune Features of the Systemic Inflammation Associated with Primary Hypercholesterolemia: Changes in Cytokine/Chemokine Profile, Increased Platelet and Leukocyte Activation. J Clin Med, 2018. 8(1).
  11. Marques, P., et al., Systemic Inflammation in Metabolic Syndrome: Increased Platelet and Leukocyte Activation, and Key Role of CX3CL1/CX3CR1 and CCL2/CCR2 Axes in Arterial Platelet-Proinflammatory Monocyte Adhesion. J Clin Med, 2019. 8(5).
  12. Landmesser, U., B. Hornig, and H. Drexler, Endothelial function: a critical determinant in atherosclerosis? Circulation, 2004. 109(21 Suppl 1): p. II27-33.
  13. Golledge, J., et al., Abdominal aortic aneurysm: pathogenesis and implications for management. Arterioscler Thromb Vasc Biol, 2006. 26(12): p. 2605-13.
  14. Davis, F.M., D.L. Rateri, and A. Daugherty, Mechanisms of aortic aneurysm formation: translating preclinical studies into clinical therapies. Heart, 2014. 100(19): p. 1498-505.
  15. Collado, A., et al., Functional role of endothelial CXCL16/CXCR6-platelet-leucocyte axis in angiotensin II-associated metabolic disorders. Cardiovasc Res, 2018. 114(13): p. 1764-1775.
  16. Rius, C., et al., Arterial and venous endothelia display differential functional fractalkine (CX3CL1) expression by angiotensin-II. Arterioscler Thromb Vasc Biol, 2013. 33(1): p. 96-104.
  17. Hotamisligil, G.S., Inflammation, metaflammation and immunometabolic disorders. Nature, 2017. 542(7640): p. 177-185.
  18. Libby, P., Inflammation in atherosclerosis. Nature, 2002. 420(6917): p. 868-74.
  19. Golledge, A.L., et al., A systematic review of studies examining inflammation associated cytokines in human abdominal aortic aneurysm samples. Dis Markers, 2009. 26(4): p. 181-8.
  20. Middleton, R.K., et al., The pro-inflammatory and chemotactic cytokine microenvironment of the abdominal aortic aneurysm wall: a protein array study. J Vasc Surg, 2007. 45(3): p. 574-80.

Collado A, Domingo E, Marques P, Perello E, Martinez-Hervás S, Piqueras L, Ascaso JF, Real JT, Sanz MJ. Oral unsaturated fat load impairs postprandial systemic inflammation in primary hypercholesterolemia patients.Front. Pharmacol. 12:656244 (2021).

Collado A, Domingo E, Piqueras L, Sanz MJ. Primary hypercholesterolemia and development of cardiovascular disorders: cellular and molecular mechanisms involved in low-grade systemic inflammation and endothelial dysfunction. Int J Biochem Cell Biol. 139:106066 (2021).

Marques P, Domingo E, Rubio A, Martinez-Hervás S, Ascaso JF, Piqueras L, Real JT, Sanz MJ. Beneficial effects of PCSK9 inhibition with alirocumab in familial hypercholesterolemia involve modulation of new immune players. Biomed. Pharmacother. 145:112460 (2022).


Conselleria de Educación, Cultura y Deporte


Prof. María Jesús Sanz, PhD


Prof. José T. Real, MD, PhD
Dr. Sergio Martinez-Hervás, MD, PhD
Dr. Patrice Marques, PhD (Contracted by the project)
Ms Elena Domingo, BSc (Predoctoral fellow)




211.736 €