Proteomic Analysis of the Superior Mesenteric Ganglion and Liver in Spontaneously Hypertensive Rats

Abstract

Spontaneously hypertensive rats (SHR) are a well accepted model of primary hypertension. Among other features common to human hypertension, these rats exhibit sympathetic hyperactivity. The neurons of the superior mesenteric ganglion (SMG) from SHR display enhanced collateral sprouting, higher firing rates and hyperinnervation of the mesenteric arteries compared to the SMG neurons from age-matched, normotensive Wistar-Kyoto (WKY) rats. Furthermore, SMG neurons in SHR are exposed to different conditions than are SMG neurons from WKY rats, including enhanced oxidative stress, increased afferent stimulation, and an altered hormonal environment. In order to identify proteins with potential involvement in the establishment or maintenance of peripheral sympathetic hyperactivity in SHR, we used proteomic techniques to search for differences in protein expression between the SMG of SHR and the SMG of WKY rats at 16 and 22 weeks of age. We found an upregulation of predominantly fetally expressed T1 domain and haptoglobin and a downregulation of serine protease inhibitor 2.1 in SHR relative to WKY rats at 16 and 22 weeks; Apolipoprotein-A1 was also found to be upregulated in 22 week SHR SMGs compared to age-matched WKY SMGs. These identifications improve our understanding of the ganglionic microenvironment in SHR and represent targets for the development of novel therapies to treat primary hypertension. Hypertension is one of the defining components of the metabolic syndrome, together with insulin resistance, visceral adiposity and hyperlipidemia. Non-alcoholic fatty liver disease (NAFLD) is also a common feature of the metabolic disorder, and thus primary hypertension and NAFLD are common comorbidities. Despite these clinical connections, very little is known about the effects of primary hypertension on hepatic physiology. We used proteomic techniques to search for evidence of significant involvement of the liver in SHR phenotype at the molecular level. We detected changes in the expression of several proteins involved in the regulation of oxidative stress and lipid metabolism which together show that the liver is strongly involved in the pathologies associated with hypertension. Our results suggest several novel mechanisms for the initiation of oxidative stress in SHR which could contribute to new advances in the treatment of metabolic abnormalities associated with hypertension.