Transgenic Rescue of Defective Cd36 Attenuates Insulin Resistance, Dyslipidemia, and Hypertension in Spontaneously Hypertensive Rats

Abstract

70 Linkage studies in spontaneously hypertensive rats (SHR) have implicated a host of different DNA sequence variants in the genetic control of blood pressure (BP) and a variety of other cardiovascular phenotypes. However, direct proof that any of these gene variants represents a true quantitative trait locus (QTL) regulating BP or any other complex trait is lacking. To directly test the identity of putative QTL in the SHR model, we have: 1) developed transgenic techniques for rescuing mutant alleles directly on the SHR background and 2) used these techniques to determine whether a gene encoding a fatty acid transporter (Cd36) truly represents a QTL that can influence the clustering of multiple cardiovascular risk factors in spontaneous hypertension. Towards these ends, we have successfully derived multiple transgenic strains of SHR (SHR-TG strains) that express the wild type allele for Cd36 on an SHR background harboring the deletion variant of Cd36 (SHR control). In these strains, low level expression of wild type Cd36 on the mutant SHR background ameliorated glucose intolerance (e.g., area under the GTT curve = 713±21 in the SHR-TG19 strain vs. 954±45 mmol/L/2hr in the SHR control strain, p