Plasma Proteomics in Cardiovascular Disease

The plasma proteome is unique in that it does not represent a particular cellular genome but, instead, reflects the collective expression of all cellular genomes. It has thus far been poorly characterized. Twenty-two of the most abundant proteins, including albumin and the immunoglobulins, comprise 99% ofthe plasma proteome mass. Many of the biologically interesting molecules relevant to cardiovascular disease (CVD) are low-abundance proteins. For example, cardiac markers such as troponin are found in the nanomolar range, insulin in the picomolar range, and tumor necrosis factor-a in the femtomolar range. In all, there are an estimated 10,000 unique proteins in the plasma, with concentrations spanning a dynamic range over 9 orders of magnitude (Fig. 5). However, some hypothesize that the entire set ofmore than 300,000 estimated human polypeptide species resulting from splice variants and posttranslational modifications is potentially represented in the plasma proteome. This is possible because the protein content of plasma consists not only of expected circulating proteins such as albumin and immunoglobulins (Igs), but also, less expectedly, ofproteins from all functional classes and cellular localizations (Fig. 6). A surprising majority of the lower-abundance proteins in plasma actually consists of intracellular or membrane proteins, present as a result of cellular signaling, apoptosis, or necrosis. Efforts to catalog the human plasma proteome using multidimensional separation strategies coupled to MS/MS have led to the identification of more than 1000 unique proteins.

Some investigators have suggested focusing on proteins whose mRNA messages contain motifs suggestive of secreted proteins. As noted, however, analysis ofthe normal human plasma proteome to date suggests the presence of a vast array of proteins that are not believed to be secreted. Many appear to be surface proteins that may be cleaved in yet unappreciated manners. In any case, because the blood has no single mRNA source, direct analysis of proteins or metabolites is necessary.

Fig. 5. Complexity of human plasma. (From ref. 5.)

In theory, all diseases lead to perturbations detectable in the blood because almost all cells communicate with plasma, which acts as the common transport conduit of cellular secretions, tissue leakage products, and waste. This makes plasma potentially the most informative proteome from a diagnostic viewpoint. There are also substantial practical advantages to analyzing human plasma for proteomics-based biomarker discovery. Blood represents an easy, inexpensive, and rapidly sampled source for study and may have particular relevance to CVDs in which blood itself is the site of pathology. Blood is also suitable for repeated sampling, both in greater quantity and with less tissue heterogeneity and sampling error compared with biopsy. Because multiple tissues ultimately contribute to the pool of circulating proteins, changes in the plasma proteome can also reflect disease involvement of other organs as well as associated pathophysiology at distant sites. For example, troponin, released from the heart, and C-reactive protein, derived from the liver, arise from different tissues but contribute jointly as complementary markers of cardiac status (7). Other yet-to-be discovered molecules, perhaps those reflecting hemodynamic compromise, might be generated by organs such as the kidneys. Thus, although analysis of specific proteomes, such as of cardiomyocytes or endothelial cells, provides clues on individual components of the disease process, the study of proteomic patterns in the blood offers a more comprehensive framework for biomarker discovery by providing global measurements of all system constituents.

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