Lipoprotein(a): Just an Innocent Bystander in Arterial Hypertension?

Abstract

Elevated plasma lipoprotein(a) [Lp(a)] is a relatively common and highly heritable trait conferring individuals time-dependent risk of developing atherosclerotic cardiovascular disease (CVD). Following its first description, Lp(a) triggered enormous scientific interest in the late 1980s, subsequently dampened in the mid-1990s by controversial findings of some prospective studies. It was only in the last decade that a large body of evidence has provided strong arguments for a causal and independent association between elevated Lp(a) levels and CVD, causing renewed interest in this lipoprotein as an emerging risk factor with a likely contribution to cardiovascular residual risk. Accordingly, the 2022 consensus statement of the European Atherosclerosis Society has suggested inclusion of Lp(a) measurement in global risk estimation. The development of highly effective Lp(a)-lowering drugs (e.g., antisense oligonucleotides and small interfering RNA, both blocking LPA gene expression) which are still under assessment in phase 3 trials, will provide a unique opportunity to reduce "residual cardiovascular risk" in high-risk populations, including patients with arterial hypertension. The current evidence in support of a specific role of Lp(a) in hypertension is somehow controversial and this narrative review aims to overview the general mechanisms relating Lp(a) to blood pressure regulation and hypertension-related cardiovascular and renal damage.

Keywords: antisense oligonucleotides; arterial stiffness; cardiovascular disease; endothelial cells; hypertension; hypertensive organ damage; lipoprotein(a); renal function; small interfering RNA; vascular smooth muscle cells.

Figure 1

Structure of lipoprotein(a). Lipoprotein(a) consists of an LDL-like core lipoprotein molecule, containing apolipoprotein-B100 to which a glycoprotein of variable molecular weight, apolipoprotein (a) [apo(a)] comprising multiple heterogeneous triple-loop structures called kringles, is covalently linked via a single cysteine–cysteine disulfide bond. K IV, kringle 4; LBS, lysine binding sites; oxPL, oxidized phospholipids.

Figure 2

Consequences of lipoprotein(a) interaction with vascular endothelium. Lp(a) crosses endothelial surfaces bound to oxidized phospholipids and binds to subendothelial structures. Once retained and oxidized, Lp(a) modifies the properties of endothelial cells that enhance expression of cell adhesion molecules and monocyte chemotaxis. Enhanced contraction and loss of contact of endothelial cells due to increased phosphorylation of myosin light chains and rearrangement of the actin cytoskeleton disrupts the integrity of the endothelial monolayer, leading to increased permeability and transendothelial migration of monocytes. Moreover, migration and adhesion of progenitor endothelial cells is impaired together with activation of endothelial cells apoptosis. K IV, kringle IV; LBS, lysine binding sites; oxPL, oxidized phospholipids; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesion molecule-1; COX-2, cyclooxygenase-2; PGE, prostaglandin E; MCP-1, monocyte chemoattractant protein-1; IL-6, interleukin-6; IL-8, interleukin-8; CCL-1, CC chemokine ligand-1.