Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, C42

Oral Communications

Non-dipper-like hypertension in sequestosome1/p62/A170 deficient mice in early phase of obesity

E. Warabi1, S. Sakai1, E. Sazuki2, T. Tomoo2, T. Yanagawa1, G. E. Mann3, T. Ishii1

1. Majors of Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan. 2. Novartis Pharma KK, Tsukuba, Ibaraki, Japan. 3. Cardiovascular Division, King's College London, London, United Kingdom.

Sequestosome1 (SQSTM1 also termed p62/A170/ZIP) is an oxidative stress-inducible protein and modulator of receptor-mediated signaling through its interaction with aPKCs (Moscat et al., 2007). SQSTM1 deficient mice exhibit mature-onset obesity (Rodriguez et al., 2006) and enhanced neointimal hyperplasia and carotid artery remodelling after arterial injury/ligation (Sugimoto et al., 2010). Obesity is associated with hypertension in man, and ambulatory blood pressure monitoring highlights an abnormal circadian blood pressure profile among obese and diabetic individuals termed ‘non-dipping blood pressure profile’. In the present study we examined whether SQSTM1 deficient mice could serve as a model of hypertension. C57BL6 (WT) and SQSTM1 knockout (KO) male mice were anaesthetized with pentobarbital (50 mg/Kg body weight; i.p. injection) and implanted with telemetry devices to monitor 24 h arterial blood pressure, heart rate and locomotor activity. The University of Tsukuba Animal Research Committee approved all animal experiments. SQSTM1 KO mice at 15 and 20 weeks of age exhibited higher resting arterial blood pressure compared to WT mice (systolic mmHg, WT light phase: 112 ± 1.9 vs KO light phase 124.2 ± 1.4, p<0.001 and WT dark phase: 128.1 ± 1.8 vs KO dark phase 130.6 ± 1.2, p<0.05, mean ± S.E.M., n= 5). Heart rate was increased in KO mice in the light phase but not dark phase (data not shown). The circadian rhythm of locomotor activity was maintained in KO mice. Over a 5-week monitoring period, the mean blood pressure of SQSTM1 KO mice was not changed significantly, although body weight increased by about 20%. Phenylephrine induced contraction and acetylcholine mediated endothelium-dependent relaxation of isolated aortic rings were not significantly different in WT and or SQSMT1 KO mice. Notably, SQSTM1 KO mice excreted higher levels of noradrenaline and adrenaline in urine, suggesting enhanced sympathetic nerve activity. Our findings suggest that SQSTM1 deficient mice provide a useful model to study pathophysiological mechanisms and potential therapy of non-dipper hypertension, known to increase the risk for future renal damages and cardiovascular events.

Where applicable, experiments conform with Society ethical requirements