title: Tyrosine hydroxylase haploinsufficiency prevents age-associated arterial pressure elevation and increases half-life in mice.
abstract: Catecholamines are essential for the maintenance of physiological homeostasis under basal and stress conditions. We aim to determine the impact of deletion of a single allele of the tyrosine hydroxylase (Th) gene might have on aging arterial pressure and life-span. We found that Th haploinsufficiency prevents age-associated increase of arterial pressure (AP) in mature adult mice, and it results in the extension of the half-life of Th-heterozygous (TH-HET) mice respect to their wild-type (WT) littermates. Heart performance was similar in both genotypes. To further investigate the lack of increase in AP with age in TH-HET mice, we measured the AP response to intra-peritoneal administration of substances involved in AP regulation. The response to acetylcholine and the basal sympathetic tone were similar in both genotypes, while norepinephrine had a greater pressor effect in TH-HET mice, which correlated with altered adrenoreceptor expression in blood vessels and the heart. Furthermore, sympatho-adrenomedular response to stress was attenuated in TH-HET mice. Plasma catecholamine levels and urine glucose increased markedly in WT but not in TH-HET mice after stress. Our results showed that TH-HET mice are resistant to age-associated hypertension, present a reduction in the sympathetic response to stress and display an extended half-life.
authors: Renal and Cardiovascular Physiopathology Unit, Department of Physiology and Pharmacology, Universidad de Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain; Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
authors: Luis
authors: L
authors: Gamella-Pozuelo
authors: Renal and Cardiovascular Physiopathology Unit, Department of Physiology and Pharmacology, Universidad de Salamanca, Spain.
authors: María T
authors: MT
authors: Grande
authors: Department of Cardiology, Hospital Clínico Universitario, Salamanca, Spain.
authors: Milagros
authors: M
authors: Clemente-Lorenzo
authors: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (CIBERDEM), ISCIII, Spain.
authors: Cayetana
authors: C
authors: Murillo-Gómez
authors: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (CIBERDEM), ISCIII, Spain.
authors: Flora
authors: F
authors: De Pablo
authors: Renal and Cardiovascular Physiopathology Unit, Department of Physiology and Pharmacology, Universidad de Salamanca, Spain; Biomedical Research Institute of Salamanca (IBSAL), Salamanca, Spain.
authors: José M
authors: JM
authors: López-Novoa
authors: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CSIC), Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas (CIBERDEM), ISCIII, Spain. Electronic address: chernandez@cib.csic.es.
authors: Catalina
authors: C
authors: Hernández-Sánchez
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D062186:Arterial Pressure; D057895:Haploinsufficiency; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D008136:Longevity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013312:Stress, Physiological; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics*
chemical_list: D014446:Tyrosine 3-Monooxygenase
keywords: Catecholamines; Hypertension; Life-span; Stress; Tyrosine hydroxylase