Aggrecan protein, early vascular lesions linked in IPAH: Study

Therapies to decrease the protein may halt disease at early stages

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Illustration shows lungs and the heart; the pulmonary arteries transport blood from the heart into the lungs.

The accumulation of aggrecan, a protein found abundantly in cartilage, may be an early response to injury in the lungs of people with idiopathic pulmonary arterial hypertension, a study suggests.

Aggrecan accumulated preferentially in blood vessel lesions marked by high blood pressure in the lungs of idiopathic PAH (IPAH) patients. IPAH indicates pulmonary arterial hypertension of an unknown cause.

The findings support the potential of therapies to decrease aggrecan levels to halt the disease at its early stages, thereby “avoiding irreversible vascular fibrosis [scarring] and remodeling,” wrote the researchers in the study, “Aggrecan Accumulates at Sites of Increased Pulmonary Arterial Pressure in Idiopathic Pulmonary Arterial Hypertension,” which was published in Pulmonary Circulation.

A feature of PAH is high blood pressure in the pulmonary arteries, which carry blood to the lungs. The condition is characterized by vascular remodeling — structural changes that narrow the blood vessels and obstruct blood flow — leading to symptoms such as shortness of breath.

Research has shown that an expansion of the extracellular matrix (ECM) — a three-dimensional network of molecules that provides structural support to surrounding cells — is seen at early PAH stages.

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How aggrecan accumulates

In fact, the accumulation of aggrecan — a core component of ECM — has been linked with swelling and blood flow disruption. Its distribution aggrecan and whether it accumulates in affected blood vessels of PAH patients remains unknown, leading an international team of researchers to analyze lung tissue samples from 11 patients with IPAH  between 2002 and 2014 that were stored at the biobank of Skane University Hospital, Sweden. The lung tissue from five donors rejected for use in transplants was also analyzed as controls.

The controls were significantly older than IPAH patients (median, 57 vs. 35 years). All IPAH patients underwent a double lung transplant, except one patient who received a single transplant. One patient had diabetes, another had high blood pressure, and a third was treated for low thyroid function.

An analysis of the tissue samples showed aggrecan accumulated in lesions composed of cellular connective tissue, which holds together and supports other tissues and organs, and was absent from regions marked by collagen, a main ECM component, or composed of elastic fibers.

Aggrecan accumulated in multiple vascular lesion types of IPAH patients, while none or little of it was seen in arterioles, small blood vessels that carry blood away from the heart, and muscle arteries of controls, analysis showed.

Aggrecan accumulated significantly more in IPAH than controls, statistical analysis confirmed. No aggrecan accumulation was seen in pulmonary veins, airways, or pulmonary parenchyma — the lung region involved in gas exchange — of IPAH lungs, however. In both patients and controls, aggrecan was detected in large elastic arteries.

Aggrecan’s production is encoded by the ACAN gene. Using a combined approach called RNAscope in situ hybridization, the researchers assessed the gene’s activity in the lung tissue samples. Gene activity is reflected in the production of messenger RNA, the molecule that carries the DNA information to the sites where proteins are produced.

ACAN activity was detected in the endothelium, the inner wall of blood vessels, and smooth muscle cells. It was also detected in tissue regions positive for alpha-smooth muscle actin (a marker of cells implicated in scarring), and von Willebrand factor, a blood protein produced by endothelial cells. Aggrecan tissue also accumulates in close proximity to and in lesions marked by increased mean pulmonary arterial blood pressure, an analysis showed.

These results suggest “ACAN expression may be an early response to injury in pulmonary angiopathy [blood vessel disease] and supports recent work showing that dysregulation of aggrecan turnover is a hallmark of arterial adaptations to altered hemodynamics [blood flow],” the study concluded.

A Conversation With Rare Disease Advocates