Novel Candidate Markers Of Hemodynamic Stress

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To discover novel pathways induced in the heart in response to hemodynamic overload in vivo, we used DNA microarray technology to characterize on a genomewide scale the acute and long-term response of the heart to pressure overload (95). We used the well-established transverse aortic constriction model of pressure overload hypertrophy in mice in which an occluding clip is surgically placed around the transverse aorta to create a hemodynamic overload on the left ventricle. LV RNA was harvested from mice 1 d and 30 wk after the imposition of hemodynamic overload, which enabled characterization of the genomewide transcriptional response ofthe heart to acute hemodynamic overload (1 d after aortic banding) as well as that during compensation and adaptation to pressure overload (30 wk after aortic banding) (Fig. 8). Transverse aortic constriction resulted in a 40-50% increase in LV mass at 30 wk compared with LV mass in sham-operated mice, demonstrating significant LV hypertrophy. Aortic-banded hearts had preserved contractile function and a concentric pattern of remodeling, indicating compensatory hypertrophy and not failure.

Fig. 8. Demonstration of process by which a candidate biomarker is revealed through genomic screening of novel genes induced by hemodynamic overload in mice in vivo. Lipocalin is dramatically induced by acute hemodynamic overload of the heart. Validation by an independent technique is an important step following microarray results. Northern blotting validates DNA microarray findings for lipocalin. (Adapted from ref. 95.)

Fig. 8. Demonstration of process by which a candidate biomarker is revealed through genomic screening of novel genes induced by hemodynamic overload in mice in vivo. Lipocalin is dramatically induced by acute hemodynamic overload of the heart. Validation by an independent technique is an important step following microarray results. Northern blotting validates DNA microarray findings for lipocalin. (Adapted from ref. 95.)

A striking initial observation in our study was that hemodynamic overload stimulated the transcription of genes unrelated to hemodynamic control, a concept that was raised at the beginning of this chapter. Functional classes of genes represented included transcription factors, signal transduction, protein processing/trafficking, protein synthesis and metabolism, immunity/inflammation, extracellular matrix, cytoskeleton, calcium binding, cobalt ion transport, apoptosis/cell death, growth inhibition, organogenesis, mRNA processing, as well as a significant number of nonannotated cDNAs of unknown functional class. Furthermore, we identified unique gene clusters that characterized acute vs chronic hemodynamic pressure overload. Thus, this study identified several previously unsuspected cardiac overload pathways to open the way for future investigation.

By identifying the secreted proteins encoded by the genes regulated by acute and chronic hemodynamic stress in vivo, novel candidate markers of hemodynamic stress may be identified. The gene most highly induced after acute hemodynamic overload was lipocalin (18-fold increased in male mice, 72-fold increased in female mice). Lipocalin is a small, secreted polypeptide that is protease resistant and has been detected in urine. Lipocalin was recently recognized as a urinary biomarker of acute renal failure owing to ischemic injury (96) as well as cisplatin nephrotoxicity (97). One function of lipocalin is to modify matrix metalloproteinase activity (98), which participates in cardiac remodeling following MI and in heart failure. Our finding of robust induction of lipocalin in the heart after acute hemodynamic stress suggests that it may be increased in the serum of patients following AMI.

Genes encoding secreted proteins that were induced by acute hemodynamic overload and further upregulated during chronic hemodynamic overload include thrombospon-

din-1 (sevenfold increased), osteoblast-specific factor 2 (sevenfold increased), biglycan (fourfold increased), and connective tissue growth factor (sixfold increased). Thrombo-spondin-1 is detected in the plasma ofhealthy individuals at low levels but can be increased when it is released from activated platelets. Many cell types other than platelets, including fibroblasts and ECs, express thrombospondin-1. Its secretion may therefore be induced in these cell types by hemodynamic stress. Thrombospondin-1 may be an inhibitor of angiogenesis through signaling cross talk with VEGF pathways. Single-nucleotide polymorphisms ofthrombospondin-1 are significantly associated with familial premature CAD and MI (99). For a review on thrombospondin-1 see ref. 100.

Gene expression studies such as the one described here are limited in their ability to identify biomarkers, because gene expression in the heart often is not reflected by changes in a protein in the blood. Thus, new techniques in proteomics (see Chapter 33), which can separate and rapidly identify different proteins, have great promise for identifying novel biomarkers. Thus far, proteomics techniques have been difficult to apply to human blood, but as these techniques evolve, it is likely that new hemodynamic markers will emerge.

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