Pleiotropic Effects of HMG-CoA Reductase Inhibitors - studies in vitro and in vivo

Cardiovascular disease (CVD) is the prime cause of death in industrialized countries, resulting from the progression of atherosclerotic lesions. An increased level of plasma cholesterol, particularly within low-density lipoproteins, is a principle risk factor, but also elevated triglycerides and low levels of high-density lipoprotein cholesterol. Recognition of dyslipidemia as a risk factor for CVD has led to an international consensus that anti-hyperlipidemic drug therapy is essential for the primary and secondary prevention in risk patients. HMG-CoA reductase inhibitors, i.e. statins, are the most common drugs used for this purpose, inhibiting the rate-limiting step in cholesterol biosynthesis. The medical significance of HMG-CoA reductase inhibitors have in recent years been expanded to include cholesterol-independent or "pleiotropic" vascular effects, including improvement of vascular endothelial function, inhibition of vascular smooth muscle cell proliferation and migration, anti-inflammatory actions, anti-oxidative effects or stabilization of vulnerable plaques. These effects have potential in the treatment of coronary artery disease in various settings, such as prevention of its onset as well as its progression. The major aim of this thesis was to contribute to the general knowledge about the pleiotropic effects of statins, particularly in relation to the vascular endothelium and to carcinogenesis. We found that fluvastatin at clinically relevant doses up-regulates transcription and translation of prostacyclin synthase and endothelial nitric oxide synthase in human vascular endothelial cells, associated with an increase in cellular production of prostacyclin (PGI2) and nitric oxide (NO), and induces rapid dilatation in isolated human arteries via contribution of endothelium derived factors like NO and PGI2. These results suggest beneficial effects of fluvastatin on endothelial maintenance in vivo and a protective role on the cardiovascular system, particularly at the level of vascular endothelium. We also show that simvastatin induces a potentially negative alteration of vascular endothelial cells both in vivo and in vitro. Exposure of clinically comparable concentrations of simvastatin led to decreased production and release of PGI2 in endothelial cells and to significantly increased urinary thromboxane A2 (TXA2) levels in healthy volunteers, possibly resulting in a shift of the balance between PGI2 and TXA2, favoring the thromboxane pathway. Fluvastatin and simvastatin were also shown to have different impact on vascular endothelial oxidative stress status, both in cultivated endothelial cells and in healthy volunteers. Compared to simvastatin, fluvastatin seems beneficial both regarding expression of anti-oxidative stress enzymes and reactive oxygen species activity in vitro and anti-oxidative capacity in vivo. The suggested anti-carcinogenic properties of statins in relation to expression of the redoxactive enzymes thioredoxin reductases (TrxR) were investigated in paper IV. We found that statin treatment decreases the hepatic expression of TrxR1 in humans and rats. In addition, the decreased TrxR1-levels were correlated with inhibited carcinogenesis in rat liver. The effect on TrxR1 levels might explain some of the anti-carcinogenic effects of statins. Overall, our results add to the conjecture that the impact on production of vascular active substances may be significantly different among the statins, and thus the consequences of statin exposure may not be drug class related but rather compound specific, highlighting the importance of more comparative studies where several statins are included. These findings add novel insight in the field of pleiotropic effects of statins and provide some insight for functional differences among statins

Single dose testosterone increases total cholesterol levels and induces the expression of HMG CoA Reductase

Abstract Background Cholesterol is mainly synthesised in liver and the rate-limiting step is the reduction of 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) to mevalonate, a reaction catalysed by HMG-CoA reductase (HMGCR). There is a comprehensive body of evidence documenting that anabolic-androgenic steroids are associated with deleterious alterations of lipid profile. In this study we investigated whether a single dose of testosterone enanthate affects the cholesterol biosynthesis and the expression of HMGCR. Methods 39 healthy male volunteers were given 500 mg testosterone enanthate as single intramuscular dose of Testoviron®--Depot. The total cholesterol levels prior to and two days after testosterone administration were analysed. Protein expression of HMGCR in whole blood was investigated by Western blotting. In order to study whether testosterone regulates the mRNA expression of HMGCR, in vitro studies were performed in a human liver cell-line (HepG2). Results The total cholesterol level was significantly increased 15% two days after the testosterone injection (p = 0.007). This is the first time a perturbation in the lipoprotein profile is observed after only a single dose of testosterone. Moreover, the HMGCR mRNA and protein expression was induced by testosterone in vitro and in vivo, respectively. Conclusion Here we provide a molecular explanation how anabolic androgenic steroids may impact on the cholesterol homeostasis, i.e. via an increase of the HMGCR expression. Increasing knowledge and understanding of AAS induced side-effects is important in order to find measures for treatment and care of these abusers.</p

Impaired renal clearance among Swedish adolescents born preterm

Aim To determine whether adolescents born before 28 gestational weeks have an increased risk for renal impairment. Methods Swedish infants, born before 28 gestational weeks in 2001 and 2002, were identified from a local register. A total of 16 children, 12 females and 4 males, were examined at 16-17 years of age with Cr-51-EDTA clearance. A comparison group (n = 26) was used. Results Most study participants (n = 13) had normal blood pressure; one individual had hypertension stage 1. All study participants had results within the reference interval for ionised calcium, parathyroid hormone, intact fibroblast growth factor-23 and for urinary albumin-to-creatinine ratio. Four out of 16 participants (25%) had a Cr-51-EDTA clearance less than 90 ml/min/1.73 m(2), indicating a reduced kidney function. Measured Cr-51-EDTA clearance values were significantly lower in the study group than in the comparison group (p = 0.0012). Five study participants (31%) were referred for further investigations. Conclusion Swedish children born before 28 gestational weeks have an increased risk of renal impairment later in life, suggesting that the kidney function in these individuals should be assessed, at least once, during adolescence.Funding Agencies|Swedish government; county councils [ALFGBG-716831, ALFGBG-678871]; ALF grants from Region Ostergotland; Agrenska research foundation</p