Genetic Ablation and Guanylyl Cyclase/Natriuretic Peptide Receptor-A: Impact on the Pathophysiology of Cardiovascular Dysfunction

Mice bearing targeted gene mutations that affect the functions of natriuretic peptides (NPs) and natriuretic peptide receptors (NPRs) have contributed important information on the pathogenesis of hypertension, kidney disease, and cardiovascular dysfunction. Studies of mice having both complete gene disruption and tissue-specific gene ablation have contributed to our understanding of hypertension and cardiovascular disorders. These phenomena are consistent with an oligogenic inheritance in which interactions among a few alleles may account for genetic susceptibility to hypertension, renal insufficiency, and congestive heart failure. In addition to gene knockouts conferring increased risks of hypertension, kidney disorders, and cardiovascular dysfunction, studies of gene duplications have identified mutations that protect against high blood pressure and cardiovascular events, thus generating the notion that certain alleles can confer resistance to hypertension and heart disease. This review focuses on the intriguing phenotypes of Npr1 gene disruption and gene duplication in mice, with emphasis on hypertension and cardiovascular events using mouse models carrying Npr1 gene knockout and/or gene duplication. It also describes how Npr1 gene targeting in mice has contributed to our knowledge of the roles of NPs and NPRs in dose-dependently regulating hypertension and cardiovascular events.