Biologically active phospholipids as potential cardiovascular drugs

Abstract

Both useful and undesirable cardiovascular properties have been associated with naturally occurring and synthetically derived phospholipids. Certain phospholipids may function physiologically (or pathophysiologically) in such processes as blood pressure regulation, cardiac rhythm, and platelet aggregation. Drugs that can modify the synthesis or degradation of endogenous phospholipid mediators or selectively mimic or block their effects may be of interest as potentially useful cardiovascular agents. This article reviews the current literature in this area and defines in chemical, biochemical, and biological terms the potential of the phospholipid-type compounds in the development of useful cardiovascular drugs.

LPA receptor signaling: pharmacology, physiology, and pathophysiology

“…However, there is a growing range of recognized chemical forms of LPA in various biological systems (31,32) that have been observed in concentrations spanning low nanomolar to micromolar levels. LPA concentrations in blood can range from 0.1 M in plasma and up to 10 M in serum, which is well over the apparent nanomolar K d of LPA [1][2][3][4][5][6] (23,(33)(34)(35) (36)(37)(38). Aside from blood, LPA has been quantifi ed in a variety of species, tissues, and fl uids, including neural tissue, cerebrospinal fl uid (CSF), seminal fl uid, urine, saliva, and aqueous humor (7,36,(39)(40)(41)(42)(43)(44)(45) (Table 1).…”

“…Two other LPA receptors, LPA 2 and LPA 3 , were subsequently discovered based on shared homology with LPA 1 . In the past ten years, three additional LPA receptors have been discovered (LPA [4][5][6] ) (19)(20)(21)(22)(23) that are members of the P2Y purinergic family (Fig. 1).…”

“…The diverse and numerous physiological effects of LPA are mediated through six currently recognized LPA receptors, LPA [1][2][3][4][5][6] : protein names LPA 1 -LPA 6 and gene names LPAR1-LPAR6 (human) and Lpar1-Lpar6 (nonhuman) (11,83). These 7-TM GPCRs couple to at least one or more of the four G ␣ proteins (G 12/13 , G q/11 , G i/o , and G s ) that initiate a variety of signaling cascades.…”

“…This expression pattern becomes more ubiquitous from E9.5-E12. 5, showing signals throughout the embryo, as well as diffuse patterns in the developing brain and choroid plexus that suggest a possible role for LPA 5 in brain development (89). Mutagenesis studies have found that several residues are likely involved in the binding of LPA to LPA 5 , including one mutant that abolished receptor activation (R2.60N) and three separate mutants that greatly reduced receptor activation (H4.64E, R6.62A, and R7.32A) (182).…”

“…LPA 5 -expressing cell lines demonstrate LPA-induced neurite retraction, stress fi ber formation, and receptor internalization in vitro through the G 12/13 pathway (21). LPA 5 can also activate G q to increase intracellular calcium levels and induce cAMP accumulation (21).…”