Inside the Artery Walls: Mechanisms and Structure of Lipoprotein(a)

The mechanisms through which apolipoprotein B (apoB) containing lipoproteins, like LDL particles, infiltrate arterial walls and contribute to atherogenesis.

Contrasting entry mechanisms:

ApoB particles, particularly LDL, invade arterial walls primarily based on their concentration gradient, with higher levels leading to increased infiltration. In contrast, Lp(a) particles can infiltrate arterial walls even at lower concentrations due to specific receptor interactions on endothelial cells and macrophages that facilitate their entry in an entirely different manner.

Pro-inflammatory effects of Lp(a):

 Lp(a) once inside the arterial wall exhibits significant pro-inflammatory properties. It activates Toll receptors on monocytes and macrophages, triggering the synthesis of various inflammatory mediators such as cytokines and chemokines. This inflammatory response is a key driver of atherogenesis within the arterial wall.

Impact on plaque stability:

Smooth muscle cells play a crucial role in stabilizing plaques by forming a protective layer around them. However, Lp(a) interferes with this process by making smooth muscle cells less effective at creating this protective matrix. Consequently, the presence of Lp(a) can contribute to plaque instability, increasing the risk of rupture and thrombotic events.

Thrombotic tendencies and platelet reactivity:

 Lp(a) not only induces inflammatory responses but also enhances platelet reactivity, promoting a more thrombotic environment within the arterial wall. This heightened thrombotic cascade increases the risk of plaque development and cardiovascular complications.

Function of Lp(a) peptides:

 Apolipoprotein(a) is composed of peptide units that contain cysteine groups with sulfur molecules. These units adhere together to form the apolipoprotein(a) molecule. The unique structure of Lp(a), including the presence of cysteine residues, may contribute to its biological activity and its impact on the inflammatory and atherogenic processes within the arterial wall.

Structure and composition:

 Apo(a) is made up of multiple units called "kringles." The term "kringle" was derived from a pastry due to the looped structure of these peptide units. In contrast to plasminogen, which has five kringles, apo(a) is a truncated form with only two kringles – kringles 4 and 5. Kringles 4 and 5 contain multiple subunits, with kringles 4 having 10 subunits and kringle 5 being a singular unit.

Genetic variation:

 The gene encoding kringle 4 can result in different numbers of subunits. This genetic variation leads to the presence of varying numbers of kringle 4 subunits in apo(a), affecting its molecular weight. A higher number of kringle 4 subunits results in a larger peptide with a higher molecular weight, while fewer repeats lead to a smaller, lower molecular weight apo(a) molecule.

Molecular weight and size terminology:

 It's important to differentiate between terms like "small" and "large" when referring to Lp(a) and apo(a). In this context, "small" and "large" refer to the molecular weight of the apo(a) peptide, not the size or diameter of the LDL particle at the core of Lp(a).