Pleiotropic effect

Although blood pressure control follows Ohm s law and seems to be simple, it underlies a complex circuit of interrelated systems. Hence, numerous physiologic systems that have pleiotropic effects and interact in complex fashion have been found to modulate blood pressure. Because of their number and complexity it is beyond the scope of the current account to cover all mechanisms and feedback circuits involved in blood pressure control. Rather, an overview of the clinically most relevant ones is presented. These systems include the heart, the blood vessels, the extracellular volume, the kidneys, the nervous system, a variety of humoral factors, and molecular events at the cellular level. They are intertwined to maintain adequate tissue perfusion and nutrition. Normal blood pressure control can be related to cardiac output and the total peripheral resistance. The stroke volume and the heart rate determine cardiac output. Each cycle of cardiac contraction propels a bolus of about 70 ml blood into the systemic arterial system. As one example of the interaction of these multiple systems, the stroke volume is dependent in part on intravascular volume regulated by the kidneys as well as on myocardial contractility. The latter is, in turn, a complex function involving sympathetic and parasympathetic control of heart rate intrinsic activity of the cardiac conduction system complex membrane transport and cellular events requiring influx of calcium, which lead to myocardial fibre shortening and relaxation and affects the humoral substances (e.g., catecholamines) in stimulation heart rate and myocardial fibre tension. 

Ray KK, Cannon CP (2005) The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes. J Am Coll Cardiol 46 1425-1430... 

Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to improve vascular outcomes due to their cholesterol-lowering effects as well as multiple pleiotropic effects. In high-risk populations, statin therapy is known to reduce the risk of vascular events such as myocardial infarction and stroke. A meta-analysis of 10 trials involving 79,494 subjects showed that statin therapy reduced the incidence of stroke by 18%, major coronary events by 27%, and all-cause mortality by 15%. The SPARCL trial recently showed that high-dose HMG-CoA reductase inhibitors prevent recurrent stroke and transient ischemic attacks. ... 

Liao JK, Laufs U. Pleiotropic effects of statins. Anna Rev Pharmacol Toxicol 2005 45 89-118. 

McCarey DW, Sattar N, Mclnnes IB. Do the pleiotropic effects of statins in the vasculature predict a role in inflammatory diseases Arthritis Res Ther 2005 ... 

Schmidt HGF has pleiotropic effects on essentially everything, but the clearest example of it being secreted in response to the damage of one organ is the fiver. It is... 

The availability of large quantities of recombinant TNF-a facilitates rigorous investigation of the effects of this cytokine on cells in vitro, as well as its systemic in vivo effects. Like most cytokines, TNF-a exhibits pleiotropic effects on various cell types. The major biological responses induced by this cytokine include ... 

K. D. Pleiotropic effects of Ubp6 loss on drug sensitivities and yeast prion are due to depletion of the free ubiquitin pool, J Biol Chem, 2003, 278, 52102-15. 

Alterations in the ubiquitin-proteasome pathway have been connected to several neurodegenerative diseases (Table 9). In some instances, mutations in specific genes have been linked to the etiology of the disease. Although the perturbations in ubiquitin-proteasome-mediated proteolysis lead to pleiotropic effects on neurons including cell death or degeneration, one of the early effects is believed to be synaptic malfunction. 

Fig. 10.13 Potential pleiotropic effects of the apoUpoprotein E (APOE) gene and its products...

Cacabelos, R. (2007) Pleiotropic effects of APOE in dementia Influence on functional genomics and pharmacogenetics. In Advances in Alzheimer s and Parkinson s disease. Insights, progress, and perspectives, Fisher, A., Hanin, 1., Stocchi, F., Memo, M. (eds.). Springer, Secaucus, NJ, in press. 

SiisstrunkU, Pidoux J,Taubert S, Ullmann A, Thompson CJ, Pleiotropic effects ofcAMP on germination, antibiotic production and morphological development in Streptomyces coelicolor, Mol Microbiol 30 33—46, 1998. 

An increasing amount of data has recently led to better insight into the pleiotropic effects of HDAC inhibitors, demonstrating that HDACs also act as regulators of cellular processes such as proliferation, apoptosis and angiogenesis through deacetylation of other protein substrates. 

Smith, R. et al. (1997). Insulin internalization and other signalling pathways in the pleiotropic effects of insulin. Int. Rev. 

Dunlap It would be an enormous amount of work to execute a screen for mutants in the FLO. When you think about it, the situation now with respect to the non-circadian rhythms represented by FLO and similar oscillators is very similar to where we all were with circadian clocks in the early 1980s we had some putative mutants that affected clock expression/function but we had no idea whether they were core circadian clock molecules or simply had pleiotropic effects on the expression of the circadian rhythm. We had no selection, only screens. As we all know it was a lot of work to convincingly show that molecules like FRQ and PER were essential for the circadian clock. I m not sure it s worth making the investment in positional cloning of an allele that might not inform you at all of a mechanism for FLO. And even if you did, since the FLO rhythm is not a circadian rhythm, where is this going to be published In our experience, a gene that affects an oscillator like the FLO that is really not circadian and that no one thinks is involved with the circadian mechanism won t interest a student. 

Rodent peroxisome proliferators exercise their pleiotropic effects in liver due to activation of PPARa. This process is essential for liver hypertrophy and... 

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