1Institute of Clinical Experimental Research, Semmelweis University, Budapest, Hungary
Introduction: Lysophosphatidic acid (LPA) is known to act on six G protein-coupled receptors (LPA1-6). It has diverse effects in the cardiovascular system including its major influence on vascular tone. Although several unsaturated LPA species are released in acute coronary syndrome, the effects of LPA on coronary vascular tone remain to be elucidated.
Aims: Our aim was to describe the effects of various unsaturated LPA species (18:1, 18:2 and 18:3 LPA) on the CF of isolated murine hearts and to identify the signaling pathways mediating the effect.
Methods and results: RT-PCR analysis of LPA1-6 mRNA abundance in segments of mouse coronaries verified the expression of each LPA receptor in the vessels. Administration of 18:1, 18:2 and 18:3 LPA (10-6 M) to the perfusion line of Langendorff perfused hearts of wild type male mice (WT) caused a substantial CF reduction (up to 35%) which resulted in the drop of left ventricular developed pressure. This effect of LPA also developed in LPA1 and LPA2 deficient mice and in the presence of LPA3 antagonists (Ki16425, VPC32183). However, deletion of LPA4 diminished the effect of LPA by 60%. The smooth muscle specific deletion of Galfaq/11 did not influence, whereas smooth muscle specific deletion of Galfa12/13 diminished by 50%, and Rho-kinase inhibition (Y27632) abolished the effect of LPA. Moreover, deletion of endothelial NO synthase enhanced, whereas inhibition of endothelin A receptor by BQ123 diminished the response of coronaries to LPA.
Conclusion: 18-LPA species are strong vasoconstrictors in the coronaries. LPA4 receptor related pathways and endothelial vasoactive substances are key factors in their action. The Galfa12/13 protein - Rho-kinase signaling pathway plays a major role in the response of the vascular smooth muscle. This process might have relevance in acute coronary events when a large amount of LPA is released due to platelet activation and plaque rupture.
Doctoral School: Basic and Translational Medicine
Program: The Mechanisms of Normal and Pathologic Functions of the Circulatory System
Supervisor: Zsuzsanna Miklos MD
E-mail address: firstname.lastname@example.org