1Universitäres Herz- und Gefäßzentrum Hamburg Klinik für Kardiologie Hamburg, Deutschland; 2Universitätsmedizin der Johannes Gutenberg-Universität Mainz Präventive Kardiologie und Medizinische Prävention Mainz, Deutschland
Background Hypertension is a major risk factor for cardiovascular diseases. In hypertensive patients, endothelium-dependent vascular relaxation in the coronary and renal arteries is often impaired. The endothelial dysfunction is an early stage of atherosclerosis, marked by impaired vasodilatation usually caused by the loss of blood vessel lining integrity. Although various factors contribute to the impartment of endothelial function in hypertension, the precise molecular mechanisms are still unclear.
CRIP1 (Cysteine-Rich Protein 1) was identified in a large-scale population study to be associated with changes in blood pressure and stroke in humans. Expression of CRIP1 is evident in various tissues, with a strong presence in the cells of blood vessels. However, the molecular involvement of CRIP1 in endothelial dysfunction and thus its contribution to hypertension requires further research.
Aim The overall aim is to elucidate the role of CRIP1 in hypertension and endothelial dysfunction. The specific focus in this project was to evaluate the association of CRIP1 with endothelial dysfunction in humans and to clarify CRIP1 impact on endothelial function in an experimental murine hypertension model.
Methods Linear regression models were used to calculate the association between CRIP1 mRNA expression and Flow-mediated vasodilation (FMD) in Gutenberg Health Study (GHS). Hypertension was induced in Crip1 deficeint and WT mice via AngII from subcutaneously implanted osmotic pumps for 28 days. The vasoreactivity of the aortic rings was then examined in response to selected vasoconstrictor (7.5 µM Prostaglandin F2α, PGF2α) and to cumulatively increasing concentrations of vasodilator stimuli (acetylcholine and glyceryl trinitrate) in the organ bath.
Results Analysis of transcriptomics data indicated an association of CRIP1 mRNA expression to endothelial function assessed by FMD (N=1487; ß=-0.72; R2=0.5; p=0.037) in humans. In AngII-treated Crip1 knockout mice we observed a significant decrease in PGF2α-induced contraction (p=0.008; ß=1.41) of the aortic vessels by 1.47-fold compared to the WT. Further, the endothelium-mediated relaxation by vasodilator acetylcholine was significantly reduced in male and female Crip1 deficient mice (average effective dose ED50 by 1.40-fold; p=0.0004), whereas endothelium-independent relaxation induced by glyceryl trinitrate was not affected.
Conclusion Our data suggest a role of CRIP1 in vascular health and the experimental data highlight a specific effect of CRIP1 on vascular function. Elucidating the contribution of CRIP1 to these molecular mechanisms could can lead to new insights into the function of CRIP1 and, in the long term to potential novel therapeutic approaches.