Cardiovascular effects of growth hormone. Studies in genetically engineered mice

Abstract

The general aim of this thesis was to enhance the understanding on the relationships between growth hormone (GH) and cardiovascular disease using genetically engineered mice. More specifically the effects of GH on blood pressure (BP), vascular and cardiac function, atherosclerosis and autonomic control of heart rate were studied. Two genetically engineered mice models were used, bovine GH transgenic (bGH) and GH receptor/binding protein knock-out mice (GHR KO). In addition a third mouse model was generated through crossbreeding of bGH and an atherosclerosis prone mouse strain, apoE-/-, yielding apoE-/-/bGH mice. bGH mice had increased mean arterial BP compared to control mice as measured by telemetry. The hypertension was not salt sensitive but associated with increased resistance of the hindquarter vasculature. Mesenteric arteries from bGH mice displayed intact endothelial function and decreased sensitivity to noradrenaline, as assessed by myograph technique, while carotid artery and aorta displayed impaired endothelial function. Treatment of the vessels with a super oxide dismutase (SOD) mimetic appeared to abolish differences in endothelium dependent vasodilation between bGH and control mice. However, aorta from young bGH mice had intact endothelial function accompanied by increased mRNA levels of SOD and endothelial nitric oxide synthase, semi quantified by real-time PCR. Heart rate responses measured by telemetry, to pharmacological challenging of the sympathetic and parasympathetic nervous system, showed that bGH mice had reduced ability for sympathetic activation but intact reflex activation of parasympathetic nervous system. bGH mice also had decreased heart rate variability and reduced noradrenaline concentrations in plasma and tissue, measured by high performance liquid chromatography. Systolic BP, measured by tail-cuff technique, was increased in female apoE-/-/bGH mice compared to apoE-/- control mice. Atherosclerotic plaque area in the thoracic aorta, quantified en face after lipid staining, was significantly increased in male apoE-/-/bGH compared to control, and tended to be increased in female apoE-/-/bGH. Interestingly, female apoE-/-/bGH had a more atherogenic serum lipid profile than male. Finally, GHR KO mice had decreased systolic BP measured by tail-cuff technique and reduced cardiac and vascular structure but intact endothelial function. Furthermore, GHR KO mice had impaired cardiac function as assessed by echocardiography. In summary, this thesis has generated new knowledge on the effects of GH on cardiovascular function and development of atherosclerosis. It has presented a novel mouse model that facilitates direct studies on the mechanism involved in GH induced atherogenesis. A further important finding is that GH appears to have profound effects on sympathetic nervous system function and tissue noradrenaline levels. This may be an interesting future target for treatment of diseases associated with autonomic dysfunction.