Pathophysiology of Atherosclerosis: How Heart Disease Really Begins - Part 2

PART 1

In the first part of this series, we saw how atherosclerosis starts with a breach in the endothelial barrier — the “first crack in the wall” — followed by the infiltration of LDL particles into the arterial lining. Once there, these lipoprotein visitors are no longer in the fast-flowing, antioxidant-rich environment of the bloodstream. Instead, they’re lodged in a relatively stagnant, enzyme-rich space where trouble can quietly brew.

This is where the real transformation begins. Isolated from normal defences, LDL undergoes chemical changes that alter its structure and behaviour. Polyunsaturated fats in its shell become vulnerable to oxidative attack, its protein backbone can be modified, and it takes on a form the immune system no longer recognises as “self.”

In this next step, we’ll explore how LDL becomes oxidised and chemically trapped within the arterial wall — and why this shift is the trigger that turns a passive deposit into an active instigator of inflammation and plaque growth.

Step 3: How LDL Becomes Oxidised and Trapped in the Arterial Wall

Now that we learned the difference between lbLDL and sdLDL and why the latter is more prone to get trapped, let’s take a deeper dive into how LDL becomes oxidised, why this matters, and what happens next in the arterial wall:

LDL Enters the Subendothelial Space

• Normally, LDL circulates in the blood delivering cholesterol and lipids to cells.

• Under endothelial dysfunction (caused by high BP, inflammation, smoking, etc.), the endothelial barrier becomes more permeable.

• LDL particles — especially small, dense ones — slip beneath the endothelium into the subendothelial space (intima layer of the artery).

Retention of LDL in the Arterial Wall

• Once inside, LDL particles bind to proteoglycans in the extracellular matrix, especially if they are small and dense.

• This retention is key — trapped LDL is now exposed longer to damaging influences.

• Think of it as a piece of food stuck between your teeth — it’s more likely to rot there than if it were swept away.

Oxidative Modification (Oxidation) of LDL

• In the subendothelial space, LDL is not protected by antioxidants like it is in plasma.

• It gets exposed to reactive oxygen species (ROS) from:

  • Activated immune cells (macrophages, neutrophils)

  • Endothelial and smooth muscle cells under stress

• Two key enzymes play a central role in initiating and accelerating LDL oxidation:

  • Myeloperoxidase (MPO)

    • Who releases it? Activated neutrophils and macrophages in sites of inflammation — like an artery wall under stress.

    • How it works:

      • MPO takes hydrogen peroxide (H₂O₂) (itself a byproduct of oxidative bursts in immune cells) and uses chloride ions to make hypochlorous acid (HOCl).

      • HOCl is like industrial bleach at a molecular scale — it doesn’t just “oxidise” gently; it aggressively chlorinates and modifies molecules.

    • Targets in LDL:

      • Surface phospholipids: PUFA tails on the LDL surface phospholipids are oxidised, forming lipid hydroperoxides.

      • ApoB-100 protein: Chlorination of tyrosine and oxidation of methionine/histidine residues distorts the protein’s structure, meaning LDL receptors can’t recognise it properly. This pushes LDL towards scavenger-receptor uptake by macrophages.

    
    

  • Lipoxygenase (LOX)

    • Who uses it? Primarily macrophages, endothelial cells, and smooth muscle cells in vascular tissue.

    • How it works:

      • LOX is an iron-containing enzyme that directly adds oxygen to cis,cis-1,4-pentadiene structures in PUFA — especially linoleic acid (C18:2, ω-6).

      • This generates lipid hydroperoxides (LOOH) — unstable, reactive molecules.

      • These hydroperoxides decompose into reactive aldehydes like 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA).

      • Aldehydes can cross-link proteins, forming a kind of molecular “superglue” that locks ApoB-100 into a damaged, non-functional state.

    
    

  • The Chain Reaction Effect

    Once either MPO or LOX damages the surface PUFA or ApoB-100, the oxidation cascade spreads:

    • Surface damage → core damage: Oxidised phospholipids generate free radicals that burrow into the LDL core, oxidising the cholesteryl esters.

    • Structural damage: ApoB-100 modifications prevent LDL recycling by the liver’s LDL receptor pathway, increasing LDL’s residence time in plasma — giving it more opportunities to penetrate arterial walls.

      
      

  • Why the body does this in the first place

    • MPO and LOX evolved as antimicrobial weapons — perfect for attacking bacterial cell walls, which also contain PUFA-like structures.

    • The problem: LDL’s lipid shell looks chemically similar to a bacterial membrane. So in the context of chronic inflammation (from insulin resistance, smoking, hypertension), immune cells keep firing at LDL — a case of friendly fire.

    
    

    Analogy:Picture LDL as a cargo truck:

    • The paint and outer shell = surface phospholipids with PUFA tails.

    • The driver’s ID badge = ApoB-100 (needed for docking at liver “warehouses”).

    • MPO is like someone splashing industrial bleach on the truck — it eats away at the paint, corrodes metal, and melts the driver’s ID badge so he’s no longer allowed in the main depot.

    • LOX is like a precise but destructive cutting torch — it slices straight into the vulnerable metal seams, producing sparks that ignite cargo inside.

    • Once the outer damage starts, the cargo (PUFA-rich cholesteryl esters) becomes rancid, and the truck is diverted to a “junkyard” (macrophages in the arterial wall), where it adds to the growing pile of wreckage (atherosclerotic plaque).

Image Credit: Researchgate

Why sdLDL ends up with more PUFA while large buoyant LDL (lbLDL) has more MUFA/SFA

1. The “aging” and remodelling effect

• When LDL circulates longer (as sdLDL tends to), it is continuously remodelled by enzymes like lecithin–cholesterol acyltransferase (LCAT), cholesteryl ester transfer protein (CETP), and hepatic lipase.

• CETP swaps cholesteryl esters in LDL for triglycerides from VLDL/HDL. Many of those cholesteryl esters in VLDL and HDL are PUFA-rich (because dietary PUFA tends to get packaged into them).

• Over time, sdLDL accumulates more linoleic acid and other PUFA in its cholesteryl ester core.

2. Dietary fat composition shows up differently in LDL sizes

• Large LDL particles are usually cleared faster and are more reflective of the liver’s initial lipid output, which often has higher MUFA/SFA content (especially if the diet is lower in seed oils and higher in SFA/MUFA).

• sdLDL forms downstream from TG-rich VLDL — and those VLDL are enriched with PUFA if the person eats a PUFA-heavy diet or is insulin resistant.

• This is because PUFA, especially omega-6, preferentially go into triglycerides and cholesteryl esters in the liver.

3. Why PUFA enrichment matters for oxidation

• PUFA have multiple double bonds → very susceptible to lipid peroxidation.

• The higher PUFA content in sdLDL’s phospholipid coat and CE core makes it chemically easier for reactive oxygen species to start the oxidation chain reaction.

• Large buoyant LDL, with more MUFA/SFA, is more stable because those fatty acids are harder to oxidise.

In short:

• Formation path: TG-rich VLDL → CETP swapping → hepatic lipase trimming

• Result: Higher PUFA content in sdLDL core & coat

• Consequence: Greater oxidation risk → stronger link to atherogenesis

Seed oils rich in linoleic acid (LA), such as soybean, corn, sunflower, safflower, and canola oil, provide the exact substrate (PUFAs) that enzymes like lipoxygenase (LOX) and myeloperoxidase (MPO) use to oxidise LDL particles.

Let’s unpack why this matters, both biochemically and practically

Linoleic Acid (LA) Is Highly Oxidation-Prone

LA is a polyunsaturated omega-6 fatty acid, and because of its multiple double bonds, it is chemically unstable and highly susceptible to lipid peroxidation.

• When LDL contains high levels of LA in its lipid layer (as it often does in people consuming seed oil-rich diets), it becomes an easy target for oxidation via:

  • LOX directly oxidising LA within LDL

  • MPO generating reactive species that further attack these unstable lipids

This leads to lipid hydroperoxides and aldehydes, which not only damage LDL but also create inflammatory byproducts like 4-HNE (4-hydroxynonenal) — a potent oxidative stress marker that can disrupt cellular function and DNA.

Seed Oils Alter LDL Composition

When diets are high in seed oils, the fatty acid composition of LDL particles shifts. The LDL lipid membrane becomes enriched in linoleic acid, making it:

• More likely to oxidise

• More likely to be retained in the arterial wall

• More likely to stimulate immune responses

In contrast, saturated fat–rich LDL tends to contain more monounsaturated and saturated fatty acids, which are much more resistant to oxidation.

Oxidised LA Metabolites (OXLAMs) Are Harmful

When LA is oxidised (either during cooking, processing, or in the body), it produces oxidised linoleic acid metabolites (OXLAMs) — such as:

• 9-HODE and 13-HODE

• 4-HNE

These have been shown to:

• Increase endothelial dysfunction

• Promote macrophage foam cell formation

• Impair mitochondrial function

• Trigger chronic inflammation and insulin resistance

Human & Animal Studies Support This Mechanism

• The Minnesota Coronary Experiment (1970s) — showed that replacing saturated fat with seed oils lowered cholesterol but increased mortality, particularly from cardiovascular causes.

• Sydney Diet Heart Study — a reanalysis showed that higher linoleic acid intake increased the risk of death from heart disease despite lowering LDL.

• Modern observational studies suggest that while omega-6 fats in whole-food forms (e.g., nuts/seeds) may not pose issues, refined seed oils — especially when heated — are linked to increased markers of inflammation and oxidation.

Bottom Line

Seed oils rich in linoleic acid feed the very oxidative pathways that convert benign LDL into dangerous oxLDL — particularly in the context of:

• Insulin resistance

• Low antioxidant status

• Chronic inflammation

• Highly processed, calorie-dense diets

If LDL is the passenger, then linoleic acid is the explosive cargo, and enzymes like MPO and LOX are the spark.

From Metabolic Syndrome to Molecular Sabotage

1. Metabolic Syndrome Sets the StageMetabolic syndrome brings together insulin resistance, hyperglycaemia, hypertriglyceridaemia, hypertension, and chronic low-grade inflammation.

• Insulin resistance keeps VLDL production high → more triglyceride-rich LDL → more small, dense LDL (sdLDL).

• Hyperglycaemia and high free fatty acids promote endothelial stress and immune cell activation.

2. Immune System Gets Trigger-Happy

• Endothelial cells in insulin resistance express more adhesion molecules (VCAM-1, ICAM-1), calling in monocytes.

• Monocytes → macrophages in the arterial intima → release inflammatory cytokines (IL-1β, TNF-α, IL-6).

• These cytokines upregulate MPO and LOX expression in vascular tissue.

3. Oxidation Risk Skyrockets

• MPO upregulation: More HOCl production, more ApoB-100 chlorination, faster phospholipid damage.

• LOX upregulation: Higher PUFA oxidation rates, more lipid hydroperoxide and reactive aldehyde production.

• This is worse when LDL particles are PUFA-rich (common in high-seed-oil diets).

4. The “Perfect Storm” for oxLDL FormationYou now have:

• More LDL particles in circulation (ApoB ↑).

• More of those particles being small and dense (easier arterial entry).

• More oxidative enzymes ready to attack PUFA tails and ApoB-100.

• Reduced antioxidant defence (low vitamin E, glutathione depletion, low paraoxonase activity on HDL).

The result: accelerated conversion of native LDL → oxidised LDL, which gets stuck in arterial walls and drives foam cell formation.

Analogy

Imagine a city with:

1. More trucks on the road (↑ ApoB).

2. Smaller trucks that fit into alleyways (sdLDL).

3. Cargo that spoils easily (PUFA-rich cholesteryl esters).

4. More vandals with blowtorches and bleach (↑ LOX, ↑ MPO).The odds of a “truck wreck” in the wrong place go way up.

Conclusion — The Turning Point: From Lipid Delivery to Inflammatory Crisis

Once LDL slips beneath the endothelium, the stage is set for its transformation. Cut off from the antioxidant-rich bloodstream, its polyunsaturated fatty acids — often enriched by a diet high in seed oils — become prime targets for oxidative attack. Myeloperoxidase (MPO) from activated immune cells and lipoxygenase (LOX) within the arterial wall act like molecular saboteurs, generating highly reactive species that damage both the fatty acid cargo and the apoB protein scaffold.

This process produces oxidised linoleic acid metabolites (OXLAMs) — toxic breakdown products of PUFA oxidation — which amplify inflammation, attract more immune cells, and further compromise the integrity of the vessel wall. In those with metabolic syndrome, high triglyceride-rich VLDL and chronic low-grade inflammation make this molecular sabotage even more likely, increasing the pool of small, dense LDL particles most prone to damage.

What began as a simple lipid transport mission has now turned into an immunological alarm signal embedded deep in the artery. In our final part, we’ll follow this chain reaction to its grim conclusion: how the immune system’s attempt to contain oxidised LDL leads to plaque formation, how these plaques can rupture, and how the body’s own clotting response can turn a silent process into a sudden, life-threatening heart attack.