New Study Seeks Specific Molecules Whose Genetic Regulation Is Altered During Aging, Contributes To Vascular Remodeling

(Augusta, GA) – Vascular disease pertains to the disorders that affect our arteries and veins. For the three most common types of vascular disease --  carotid, aortic and peripheral – aging is a major risk factor. Recent studies suggest that pathological changes not only predispose the vasculature to disease but also impair compensatory adaptations to various stimuli including shear force and injury. Other studies have demonstrated a progressive increase in oxidative stress, activation of inflammatory mediators, and increasing endothelial dysfunction in both humans and animals. 

Yet individuals and certain rodent strains display different degrees of “physiological aging” at a given chronological age—suggesting a genetic component in the aging process.  Aging within the vasculature is characterized by remodeling events similar to those observed in atherosclerosis.  Although this vascular aging may predispose the vasculature to disease, the mechanistic basis for this remodeling is presently not understood.  One approach to understanding the progressive changes that occur in the vasculature during aging is to evaluate gene expression in vessels that display varying degrees of aging/remodeling.  Such a comprehensive genetic analysis would identify specific molecules involved in the aging process.  From this analysis novel pathways that regulate the vascular pathologies that develop with aging could be identified as well as potential markers of vascular aging.

A New Study

Against this backdrop a team of researchers has undertaken a study to identify specific molecules whose genetic regulation is altered during aging and that contribute to age-dependent vascular remodeling.  Their results are consistent with the current concept that atherosclerosis is an inflammatory process, and suggests that the Fisher 344/Brown Norway F1 hybrid rat (F344xBNrats) may be a good model for studying the vascular changes that occur early in the development of atherosclerosis. 

The authors of a new study entitled, “Alterations in Gene Expression During Progressive Aging in Rat Thoracic Aorta,” are Steven J. Miller and Joseph L. Unthank, Methodist Research Institute, Clarian Health, Indianapolis, IN and William C. Watson and Kimberly A. Kerr, Department of Surgery, Indiana University School, of Medicine, Indianapolis, IN. They will present their findings during the upcoming scientific conference, Understanding Renal and Cardiovascular Function Through Physiological Genomics, a meeting of the American Physiological Society (APS) (www.the-aps.org), being held October 1-4, 2003 at the Radisson Riverfront Hotel and Convention Center, Augusta, GA.

Methodology

In their earlier work, the researchers used oligonucleotide microarray analysis to investigate progressive age-mediated changes in gene expressions to demonstrate that vascular remodeling occurs in rat aorta with progressive aging. In the current study, thoracic aorta was harvested from 3-, 6-, 15-, and 28-month old F344xBNrats and total RNA was isolated. Microarray analysis was conducted using a standard protocol. Four biologic replicates were used for each age.

Results

The researchers found:

• that the total number of genes with significant (p<0.01) changes in expression increased with progressive aging compared to 3-month old rats (11, 21, and 277 genes at 6, 15, and 28 months, respectively);

• inflammatory-associated adhesion molecules ICAM-1 and VCAM-1 had significantly (p< 0.01) increased expression at 28 vs. 6 months (2.1x and 3.7x, respectively), as well as 28 vs. 15 months (1.6x and 2.0, respectively);

• ICAM-1/VCAM-1 expression also increased at 15 vs. 6 months, but was not statistically significant; and

• other functional groups of genes that were significantly altered with age at 28 vs. 6 months included increased growth factor expression (FGF-1, TGF-beta-1) and decreased stress protein expression (HSPs 10, 60, 90).

Conclusions

These results demonstrate a progressive age-related increase in thoracic aorta gene expression for adhesion molecules that participate in inflammatory-mediated pathologies, as well as altered expression for selected groups of molecules involved in vascular remodeling.

Next Steps

Future work will investigate differences in gene expression between vessel types and rat strains known to vary in their capacity to remodel during aging.  This should allow the researchers to identify additional molecules and pathways involved in the progressive development of vascular pathologies.  Accordingly, the results of such studies will provide important new information regarding the genetic basis for vascular aging and lead to additional studies that will identify new targets for diagnosis and interventional therapies for preventing and reversing these pathological changes.  This is significant because the majority of current pharmaceuticals was developed for treatment of young, and not aged, adults, who represent a rapidly increasing proportion of the population.

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The American Physiological Society (APS) is one of the world’s most prestigious organizations for physiological scientists. These researchers specialize in understanding the processes and functions by which animals live, and thus ultimately underlie human health and disease.  Founded in 1887 the Bethesda, MD-based Society has more than 11,000 members and publishes 3,800 articles in its 14 peer-reviewed journals each year.

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EDITOR’S NOTE: Members of the press are invited to attend the conference and interview the researchers in person or by phone. Please contact Donna Krupa at (703) 527-7357 (office); (703) 967-2751 (cell) or djkrupa1@aol.com (email) for more information.