Papel de la cardiotrofina-1 en la hipertrofia ventricular izquierda del paciente hipertensoestudios genéticos y moleculares

Résumé

Hypertensive heart disease (HHD) comprises the structural and functional alterations that the heart suffers as a response to the stress of increased blood pressure. The most characteristic clinical expression of HHD is left ventricular hypertrophy (LVH). Cardiotrophin-1 (CT-1) is a cytokine that is critically involved in the development of LVH, as clinical and experimental evidences indicate. We have searched for genetic variants of the human CT-1 gene (CTF1) and we have identified two polymorphisms, the 1742(C/G) variant in the first intron and the 6662(C/T) variant in the third exon. Our data indicate that the 1742(C/G) polymorphism is associated with hypertension and with the prevalence of LVH. We have found that the 1742(C/G) polymorphism is a significant determinant of the serum levels of CT-1 and also of the left ventricular mass index, after adjusting for confounding factors such as age, sex, systolic blood pressure and antihypertensive treatment. Collectively, our data suggest that the GG genotype for the 1742(C/G) polymorphism may be a protective against LVH in essential hypertension. We also have carried out molecular studies in which we have found out that hypoxic stress increases the transcriptional activity of the human promoter of CT-1 gene, in HL-1 cardiomyocytes. These results are highly interesting due to the relevance of hypoxia in the context of hypertension and in the development of LVH. We have characterized that the main transcription factor involved in the regulation of human CT-1 promoter by hypoxia is HIF-1. We determined that the mechanisms by which HIF-1 regulates the human CT-1 promoter include the direct interaction between HIF-1 and two functional hypoxia response elements of the promoter sequence.