Genetic modifiers of hypertension, atherosclerosis and cardiac hypertrophy in mice.

摘要

Hypertension (HTN), atherosclerosis and cardiac hypertrophy (CH) are complex diseases that are largely genetically determined. However, both the specific genes that confer increased susceptibility and the nature of the relationship between these conditions remain mostly a mystery. Since human studies have been difficult because of confounding variables and complex genetics we used genetically modified mice to examine this relationship.; We generated two mouse models combining HTN and atherosclerosis: hypertensive mice [by lack of either endothelial nitric oxide synthase, eNOS, or natriuretic peptide receptor A (NPRA), Npr1] were crossed with mice that are atherosclerotic (by lack of apolipoprotein E, Apoe). Compared to normotensive Apoe−/− mice, eNOS−/−, Apoe−/− mice have increased atherosclerosis which is ameliorated by enalapril or furosemide treatment. Npr1 −/−, Apoe−/− also have enhanced atherosclerosis. While eNOS−/− , Apoe−/− mice have normal heart size, Npr1−/−, Apoe−/− mice have a high incidence of neonatal death and much greater CH than either Npr1 −/− or Apoe−/− mice. Thus, these studies suggest that HTN is directly related to atherosclerosis but does not always affect CH.; Npr1−/− mice have CH disproportionate to their moderate increase in BP and have larger than normal hearts at birth which persists throughout life. There is a gene dosage effect as Npr1−/− mice have moderate increases in BP and heart weight. Chronic BP normalization does not decrease the CH in Npr1−/− mice. However, in response to any total pressure overload, Npr1−/− mice have a much greater increase in CH than Npr1 −/− mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions on the heart independent of BP.; HTN and CH are multigenic diseases caused by small mutations in numerous genes. Our studies in mice suffest that the human NPRA gene, NPR1 , is a candidate gene for these conditions. We determined the genomic sequence of NPR1 and identified several common polymorphisms this gene. These polymorphisms will be important in testing whether common variants in NPR1 contribute to complex but common disease conditions in humans.