The counter-regulatory axis of the renin-angiotensin system (RAS) is a novel therapeutic target in cardiovascular disease. Pathophysiological effects mediated via angiotensin II (Ang II) are well established in regulation of blood pressure, cardiac and vascular remodeling, and renal sodium handling, which lead to disorders such as hypertension and associated end-organ damage, atherosclerosis and heart failure. The counter-regulatory axis of the RAS is centered on the angiotensin-converting enzyme 2/angiotensin-1-7 (Ang-[1-7])/Mas receptor axis and has been shown to inhibit many detrimental phenotypes in cardiovascular disease. More recently, an alternative peptide, angiotensin-(1-9) (Ang-[1-9]), has been reported as a potential new member of this axis. This review will discuss the cardiovascular regulatory roles of Ang-(1-7) and Ang-(1-9) in the counter-regulatory axis of the RAS, and the potential for new therapeutic approaches in cardiovascular disease.
Recent studies have generated interest in the function of human adenovirus serotype 5 (HAdV-5) hexon: factor X (FX) binding and subsequent hepatocyte transduction and interaction with the immune system. Here, we retargeted adenovirus serotype 5 vectors, ablated for FX interaction, by replacing amino acids in hexon HVR7 with RGD-4C or inserting the peptide into the fibre HI loop. These genetic modifications in the capsid were compatible with virus assembly, and could efficiently retarget transduction of the vector via the αvβ3/5 integrin-mediated pathway, but did not alter immune recognition by pre-existing human neutralizing anti-HAdV-5 antibodies or by natural antibodies in mouse serum. Thus, FX-binding-ablated HAdV-5 can be retargeted but remain sensitive to immune-mediated attack. These findings further refine HAdV-5-based vectors for human gene therapy and inform future vector development.
We have studied the effect of caloric intake on metabolic rate in normal and burned (20-25% body surface area, BSA) guinea pigs. Food intake was standardized by means of infusing a liquid diet (48 kcal/day) through chronic gastrostomy tubes continuously for 16 hours per day. We found that feeding control animals a diet insufficient to meet their daily caloric requirements nevertheless resulted in a significantly higher basal oxygen consumption (VO2) 8 hours after food than during fasting. The incremental increase in basal VO2 induced by feeding burned animals (20-25% BSA) was even greater than in controls. Thus, although basal VO2 was similar in control fasted and burned-fasted animals, basal VO2 in burned-fed animals was significantly greater than in control-fed animals.
The effects of meperidine on operant behavioral thermoregulation were investigated using a convective thermal controller and mice trained to alternate at will the thermal-drive condition, changing it from an air flow of 15 degrees C to one of 45 degrees C, and vice versa. Administration of 15 mg/kg meperidine resulted in significantly lower response rates, a significantly larger fraction of time spent in one (mostly cold) drive condition, and significantly lower body temperatures than administration of saline. In a second experiment the animal was automatically returned to the hot-drive condition every 3 min unless it had been exposed to this condition in the previous 0.4 min although otherwise it remained free to alternative drive conditions at will. Under these conditions, meperidine-treated animals also spent significantly more time in cold drive and had significantly lower body temperatures than control animals, in spite of lower response rates. Pretreatment with 4.5 mg/kg tranylcypromine (4 h prior) did not significantly alter the effects of meperidine administration in either experiment.
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