Substitution of brown Norway chromosome 16 preserves cardiac function with aging in a salt-sensitive Dahl consomic rat.

摘要

It has been very difficult to determine the genetic factors that control the progression of left ventricular hypertrophy (LVH) to heart failure despite extensive study in animal models. The studies in this dissertation have characterized a consomic rat model of LVH resulting from the introgression of chromosome 16 from the Brown Norway (BN) rat onto the genetic background of the Dahl salt-sensitive (SS/Mcwi) rat by marker assisted breeding. The SS-16BN/Mcwi consomic rats are normotensive, but display LVH equivalent to the hypertensive SS/Mcwi rats at early ages. Our specific goal was to determine the effect of LVH on cardiac function and remodeling in the SS-16BN/Mcwi consomic rats by measuring LV.;The substitution of BN chromosome 16 in the SS/Mcwi rat results in resistance to age related deterioration in cardiac function greater than that seen in either parental strain. Aging SS-16BN/Mcwi rats showed no evidence of heart failure or impaired cardiac function upon extensive analysis of left ventricle function by echocardiography and pressure-volume relationships, while their parental SS/Mcwi experienced deterioration in function. In addition aging SS-16BN/Mcwi did not exhibit tissue remodeling common to pathological hypertrophy such as increased fibrosis and reduced capillary density in the myocardium. In fact, SS-16BN/Mcwi were better protected from developing LV fibrosis with age than either the hypertensive SS/Mcwi or normotensive BN parental strains. This suggested that a gene or genes on chromosome 16 may be involved with both blood pressure regulation and preservation of cardiac function with aging.;The consomic rat model, in combination with its genetic controls, provides a number of potential advantages over knockout or surgical models of hypertrophy and heart failure. The SS-16BN/Mcwi rat provides a model of resistance to progression to heart failure that occurs because of a combination of naturally occurring alleles in SS/Mcwi and BN rats. The genetic similarity of the SS-16BN/Mcwi and the parental SS/Mcwi rat, along with the availability of the chromosome 16 donor BN rat, provides unique opportunities to characterize both the progression to heart failure and the identity of genes on chromosome 16 contributing to protection.;Microarray studies were completed on both the parental SS/Mcwi and consomic SS-16BN/Mcwi to begin to uncover the mechanism of LV function preservation in the consomic rat. The differentially expressed genes were analyzed to identify functionally relevant signaling pathways. While several signaling pathways showed differential regulation between the SS/Mcwi and SS-16BN/Mcwi, the relationship of gene/protein expression to observed phenotypes suggested that the preservation of cardiac function in the SS-16BN/Mcwi results primarily from a rescued angiogenic potential provided by BN chromosome 16. The preserved capillary density in the SS-16BN/Mcwi would result in sustained oxygenation of the myocardial tissue with reduced hypoxia related cell damage and apoptosis commonly associated with heart failure.