adrenomedullin and lysophosphatidic-acid

Phospholipid derivatives, such as lysophosphatidic acid (LPA), exhibit mitogenic effects on mesenchymal stem cells; however, the molecular mechanism underlying this stimulation has yet to be identified. The aims of the present study were as follows: To evaluate the stimulatory effects of LPA on the proliferation and migration of adipose‑derived stem cells (ASCs); to study the association between reactive oxygen species (ROS) and LPA signaling in ASCs; and to investigate the microRNAs upregulated by LPA treatment in ASCs. The results of the present study demonstrated that LPA increased the proliferation and migration of ASCs, and acted as a mitogenic signal via extracellular signal‑regulated kinases 1/2 and the phosphoinositide 3‑kinase/Akt signaling pathways. The LPA1 receptor is highly expressed in ASCs, and pharmacological inhibition of it by Ki16425 significantly attenuated the proliferation and migration of ASCs. In addition, LPA treatment generated ROS via NADPH oxidase 4, and ROS were able to function as signaling molecules to increase the proliferation and migration of ASCs. The induction of ROS by LPA treatment also upregulated the expression of miR‑210. A polymerase chain reaction array assay demonstrated that the expression levels of adrenomedullin and Serpine1 were increased following treatment with LPA. Furthermore, transfection with Serpine1‑specific small interfering RNA attenuated the migration of ASCs. In conclusion, the present study is the first, to the best of our knowledge, to report that ROS generation and miR‑210 expression are associated with the LPA‑induced stimulation of ASCs, and that Serpine1 mediates the LPA‑induced migration of ASCs. These results further suggest that LPA may be used for ASC stimulation during stem cell expansion.

Topics: Adipose Tissue; Adrenomedullin; Cell Movement; Cell Proliferation; Gene Expression Regulation; Humans; Lysophospholipids; MicroRNAs; Plasminogen Activator Inhibitor 1; Reactive Oxygen Species; Receptors, Lysophosphatidic Acid; Stem Cells

Lysophosphatidic acid (LPA) is a bioactive phospholipid having growth factor-like activity on fibroblasts and is involved in cardiovascular diseases such as hypertension and heart failure by inducing vascular remodeling, characterized by fibroblast proliferation and migration in adventitia. Among various bioactive factors that LPA works with, adrenomedullin (ADM) is a multiple functional peptide with an important cytoprotective effect against cardiovascular damage. We studied rat aortic adventitia to explore the possible paracrine/autocrine interaction between endogenous ADM and LPA. LPA stimulation of the adventitia to secrete ADM and express its mRNA was concentration dependent. ADM inhibited LPA-induced proliferation in adventitial cells and attenuated the activity of mitogen-activated protein kinase (MAPK) stimulated by LPA. In contrast, treatment with specific antagonists of the ADM receptor potentiated the LPA-induced proliferation in adventitial cells. We concluded that LPA stimulates the adventitia to produce and secrete ADM, which in turn regulates the vascular biological effects of LPA.

Topics: Adrenomedullin; Animals; Cell Proliferation; Connective Tissue; Cyclic AMP; DNA; Dose-Response Relationship, Drug; Enzyme Activation; Gene Expression Regulation; Lysophospholipids; Mitogen-Activated Protein Kinases; Paracrine Communication; Peptides; Rats