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180 - Steroid Hormones
- from PART IV - DIAGNOSIS AND TREATMENT
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- By James K. Liao, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Edited by William C. Aird, Harvard University, Massachusetts
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- Book:
- Endothelial Biomedicine
- Published online:
- 04 May 2010
- Print publication:
- 03 September 2007, pp 1674-1681
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Summary
Many cellular responses to steroid hormones involve the transcriptional modulation of target genes by the prototypical nuclear receptor, the steroid hormone receptor. In the classic model of steroid hormone action, steroid hormones such as estrogen and glucocorticoids function essentially as ligand dependent transcription factors by either activating or repressing gene expression through direct interactions with DNA or other transcription factors. However, recent evidence suggests an important role for the nontranscriptional effects of steroid hormones in the vascular system, particularly in endothelial cells (ECs), where they mediate the rapid activation of endothelial nitric oxide synthase (eNOS).
For example, the activated estrogen receptor (ER) mediates signaling cascades that culminate in direct protective effects such as vasodilation, inhibition of response to vessel injury, limiting myocardial injury after infarction, and attenuating cardiac hypertrophy. These effects of ER are mediated by rapid signaling pathways at the membrane and in the cytoplasm via various second messengers including protein kinases. Similarly, the nontranscriptional actions of the glucocorticoid receptor (GR) involve the rapid activation of protein kinases, such as phosphoinositide 3-kinase (PI3K) and Akt, leading to the activation of eNOS. These rapid, nongenomic pathways of estrogen and glucocorticoids may provide the pharmacological basis for future therapeutic approaches to cardiovascular diseases (Table 180–1).
SIGNALING PATHWAYS MEDIATED BY STEROID HORMONES
The study of steroid hormone action has provided many important insights into the regulation of cellular functions by nuclear receptors and, at the same time, has revealed surprising levels of biological complexity.
179 - Statins
- from PART IV - DIAGNOSIS AND TREATMENT
-
- By James K. Liao, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
- Edited by William C. Aird, Harvard University, Massachusetts
-
- Book:
- Endothelial Biomedicine
- Published online:
- 04 May 2010
- Print publication:
- 03 September 2007, pp 1668-1673
-
- Chapter
- Export citation
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Summary
Risk factors for cardiovascular disease, such as cigarette smoking, hypertension, and elevated serum lipid levels impair endothelial function and lead to the development of atherosclerosis. Recent studies suggest that 3-hydroxy-3-methylglutaryl- CoA (HMG-CoA) reductase inhibitors or statins reduce cardiovascular events, in part, by improving endothelial function. Statins reduce plasma cholesterol levels, thereby decreasing the uptake of modified lipoproteins by endothelial cells (ECs). There is increasing evidence, however, that statins may also exert effects beyond cholesterol lowering. Many of these cholesterol-independent or “pleiotropic” vascular effects of statins appear to involve restoring or improving endothelial function by increasing the bioavailability of nitric oxide (NO), promoting re-endothelization, reducing oxidative stress, inhibiting inflammatory responses, and increasing fibrinolysis. Thus, the endothelium-dependent effects of statinsmay contribute to many of the beneficial effects of statin therapy in cardiovascular disease.
STATINS AND ENDOTHELIAL FUNCTION
Statins inhibit an early rate-limiting step in cholesterol biosynthesis (Figure 179.1). This leads to increased hepatic low density lipoprotein (LDL) receptors and enhanced uptake of cholesterol by the liver. Indeed, therapeutic doses of statins potently reduce serum cholesterol levels in humans, and several large clinical trials have demonstrated that inhibition of HMG-CoA reductase by statins markedly decreases the incidence of cardiovascular events in hypercholesterolemic individuals (1,2). Because of the strong association between elevated serum cholesterol levels and coronary atherosclerotic disease, the reduction of serum cholesterol levels by statins has been proposed to be the predominant mechanism underlying the beneficial effects of these drugs. Indeed, acute plasma LDL aphaeresis improves endothelium-dependent vasodilatation (3), suggesting that statins could restore endothelial function, in part, by lowering serum cholesterol levels.