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A proteome atlas for an untreatable heart disease

As occurs with arteriosclerosis, in which deposits of cholesterol, fat and other substances gradually form plaque in the arteries and constrict blood flow, heart valves can also suffer problems over time. One of the most significant is calcific aortic valve disease (CAVD) which, as its name indicates, consists of the deposition of calcium in the aortic valve of this vital organ.

This complication normally affects people over 65 years of age, with some studies suggesting that by this age up to 25% of individuals have developed CAVD. Its origin has been linked to hereditary factors, deposits of lipoproteins and chronic inflammation, and it may also appear in younger individuals concomitantly with other health conditions such as kidney disease.

In cases in which the valve’s lumen has become very narrow, causing stenosis, surgery may be necessary to treat CAVD. The intervention is useful to replace the affected valve, a treatment that has an 80% three-year survival rate. Nevertheless, as of today many of the biological mechanisms involved in the onset of this disease are unknown, and there are no safe or effective drug therapies to manage it.

Heart organ
Source: Pixabay

To discover what was happening at the molecular level to patients who suffered calcific aortic valve disease, a group of scientists from the United States has mapped out an atlas on the proteome of this pathology. Their goal was to analyze gene expression and the distribution of proteins in aortic valves taken from CAVD patients who had undergone a valve replacement. Their results were recently published in Circulation.

After removing 25 aortic valves affected by calcification, the researchers carried out a study applying proteomics and transcriptomics techniques. Under the guidance of near-infrared molecular imaging, they divided the samples depending on the pathological stage they were in (no disease, fibrotic or calcified). The valves were later used to carry out a transcriptional analysis and tissue layer tandem mass tagging (TMT) proteomics, a technique in which valves from autopsies made up the control group.

“AV whole tissue label-free peptide samples were examined with the Q Exactive mass spectrometer. AV tissue layer TMT and in vitro migration label-free peptide samples were analyzed with the LTQ-Orbitrap Elite mass spectrometer,” state the authors in their article. Their strategy led the researchers to determine protein-protein interaction networks and identify the molecules related with CAVD. “We have been able to produce a precise omics-level molecular atlas of the aortic valve and the molecular network of calcific aortic valve disease,” states Florian Schlotter, lead author of the study.

Source: Wikimedia

That is how they discovered molecules related with every pathological stage: non-diseased stage (ANXA3, BST1, FGL2, IL17D), fibrotic stage (AOC3, CCDC80, CILP, CRTAC1, GFAP, HTRA3, PCOLCE2, PLA2G2A, PRG4, TUBB2B), and calcific stage (A2M, CMA1, CORO1A, HCLS1, LCP1, MZB1, SERPINA1, VWF). “Together, our multi-pronged omics assessment of CAVD has led us to a number of new insights into the pathobiology of this poorly understood disease,” says Elena Aikawa, director of the Heart Valve Translational Research Program at the Brigham and Women’s Hospital de Boston, in a press release.

The use of technological services and the generation of omics data has made it possible for researchers to identify key molecules that represent “potential therapeutic targets”, in Schlotter’s words, to eventually develop drug therapies to treat CAVD. Their research is the first to track the molecular regulatory networks in this pathology, even though they have achieved it with a low number of samples. The usefulness of such a proteomic atlas may not stop at this pathology, so prevalent in the elderly population; recently, the strategy has been applied to other diseases such as osteoarthritis.