Elevated Systolic Blood Pressure in Male GH Transgenic Mice Is Age Dependent

Abstract

Acromegaly is associated with an increased incidence of cardiovascular disease. Transgenic mice expressing bovine GH (bGH) gene have previously been used to examine the effects of chronic GH stimulation on cardiovascular function. Results concerning systolic blood pressure (SBP) in bGH mice are conflicting. We hypothesized that these discrepancies may be the result of the various ages of the mice used in previous studies. In the current study, SBP was assessed monthly in male bGH mice from 3-12 months of age. Factors known to alter blood pressure were assessed during this time and included: levels of brain natriuretic peptide (BNP) and glucose homeostasis markers, and renal levels of angiotensin-converting enzyme 2 and endothelial nitric oxide synthase. Beginning at 6 months of age bGH had increased SBP compared with wild-type controls, which remained elevated through 12 months of age. Despite having increased blood pressure and cardiac BNP mRNA, bGH mice had decreased circulating levels of BNP. Additionally, bGH mice had an age-dependent decline in insulin levels. For example, they were hyperinsulinemic at 3 months, but by 11 months of age were hypoinsulinemic relative to wild-type controls. This decrease in insulin was accompanied by improved glucose tolerance at 11 months. Finally, both angiotensin-converting enzyme 2 and endothelial nitric oxide synthase expression were severely depressed in kidneys of 11-month-old bGH mice. These results indicate that elevated SBP in bGH mice is dependent on age, independent of insulin resistance, and related to alterations in both the natriuretic peptide and renin-angiotensin systems.

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

“…To clarify the direct effects of GHR on cardiac tissue, our laboratory generated a tamoxifen-inducible cardiac-specific GHR disrupted (iC-GHRKO) mouse line at 4-month-old (309,310). No difference in baseline or in postdobutamine stress test echocardiography measurements or longitudinal systolic blood pressure measurements were found when compared with controls.…”

Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice

“…Glucose intolerance, with improved systemic insulin sensitivity [as measured by insulin tolerance tests (ITT)], is also observed in mouse models with GHD (7) and growth hormone (GH) resistance (11,13). Notably, the opposite metabolic phenotype (improved glucose tolerance with normal/reduced insulin sensitivity) is observed in mice with elevated heterologous (6) or endogenous (10) GH levels.The disconnect between systemic insulin sensitivity and glucose tolerance observed in mouse model systems and humans with isolated changes in GH production and signaling (6,7,10,13,15,22,27,32) suggests GH might differentially alter tissue-specific insulin sensitivity and/or change ␤-cell function/ mass. To differentiate between these possibilities, we have performed studies using mice with adult-onset, isolated GHD [AOiGHD (22)] and mice with elevated endogenous GH levels due to somatotrope-specific loss of IGF-I and insulin receptors [HiGH (10)].…”

“…The disconnect between systemic insulin sensitivity and glucose tolerance observed in mouse model systems and humans with isolated changes in GH production and signaling (6,7,10,13,15,22,27,32) suggests GH might differentially alter tissue-specific insulin sensitivity and/or change ␤-cell function/ mass. To differentiate between these possibilities, we have performed studies using mice with adult-onset, isolated GHD [AOiGHD (22)] and mice with elevated endogenous GH levels due to somatotrope-specific loss of IGF-I and insulin receptors [HiGH (10)].…”

STAT5a/b contribute to sex bias in vascular disease: A neuroendocrine perspective

“…103 We note that GH and STAT5 are involved in vascular SMC proliferation, motility and remodeling after injury, [71][72][73][74][75][77][78][79][80] and that transgenic male mice overexpressing bovine GH developed hypertension between 5 and 6 months of age, independent of their bodyweight. 110 This hypertension then persisted long-term. 110 Such observations, together with our data in Figure 7, implicate the GH-STAT5 axis in systemic vascular biology.…”

“…110 This hypertension then persisted long-term. 110 Such observations, together with our data in Figure 7, implicate the GH-STAT5 axis in systemic vascular biology. The extent to which the GH-STAT5 axis contributes to sex bias in systemic vascular remodeling remains an open question, but one that can now be addressed using the conditional SMC-specific STAT5a/b¡/¡ mice.…”