Ancient DNA from Nubian and Somali wild ass provides insights into donkey ancestry and domestication.

Genetic data from extant donkeys (Equus asinus) have revealed two distinct mitochondrial DNA haplogroups, suggestive of two separate domestication events in northeast Africa about 5000 years ago. Without distinct phylogeographic structure in domestic donkey haplogroups and with little information on the genetic makeup of the ancestral African wild ass, however, it has been difficult to identify wild ancestors and geographical origins for the domestic mitochondrial clades. Our analysis of ancient archaeological and historic museum samples provides the first genetic information on the historic Nubian wild ass (Equus africanus africanus), Somali wild ass (Equus africanus somaliensis) and ancient donkey. The results demonstrate that the Nubian wild ass was an ancestor of the first donkey haplogroup. In contrast, the Somali wild ass has considerable mitochondrial divergence from the Nubian wild ass and domestic donkeys. These findings resolve the long-standing issue of the role of the Nubian wild ass in the domestication of the donkey, but raise new questions regarding the second ancestor for the donkey. Our results illustrate the complexity of animal domestication, and have conservation implications for critically endangered Nubian and Somali wild ass.

Gene therapy for hypertension: antisense inhibition of the renin-angiotensin system.

Despite excellent antihypertensive drugs on the market, about 70% of all hypertensive patients do not have their blood pressure under control. This is due to problems of compliance, largely because of having to take drugs daily and side effects. We propose an antisense therapy for hypertension because antisense treatment can provide long-lasting, highly specific control of blood pressure. Antisense to oligonucleotides can be designed to inhibit genes that produce proteins known to be overactive in hypertension and that are proven targets of current drug treatments. These include beta1-receptors, angiotensin-converting enzyme (ACE), and angiotensin type 1 receptors (AT1R). Antisense oligonucleotides are short (12-20 bases), single strands of DNA. They are designed to hybridize to specific mRNA and prevent translation of the target protein. Antisense inhibition of ACE, angiotensinogen or AT1R genes components of the renin-angiotensin system effectively reduce high blood pressure in animal models of hypertension. These include a genetic model (SHR) a surgical model (2KIC), and an environmental model (cold-induced hypertension). In all models, a single systemic administration of antisense decreased blood pressure by about 25 mmHg, and the effect could last up to 1 mo. No toxic effects of repeated antisense treatment were found. The results indicate that antisense therapy could be used for human hypertension and provide long-term protection that would increase compliance of patients.

The predominant role of brain angiotensinogen and angiotensin in environmentally induced hypertension.

Rats exposed chronically to a cold environment (5 degrees C/4 degrees F) develop hypertension. This cold-induced hypertension (CIH) is a non-genetic, non-pharmacological, non-surgical model of environmentally induced hypertension in rats. The renin-angiotensin system (RAS) appears to play a role in both initiating and/or maintaining the high blood pressure in CIH. The goal of the present study was to evaluate the role of central and peripheral circulating RAS components, angiotensinogen (AGT), angiotensin-converting enzyme (ACE) and angiotensin (Ang) II, in CIH. Seventy-two Sprague-Dawley adult male rats were used. Thirty-six rats were kept in cold room at 5 degrees C while the other 36 were at 24 degrees C as controls for 5 weeks. Systolic blood pressure (SBP) was recorded by tail cuff. The SBP was increased in rats exposed to cold within 1 week, and this increase was significant for the next 2-5 weeks of the cold exposure (p<0.01). Three subgroups of the cold-treated and control rats (n=12) were sacrificed at 1, 3 and 5 weeks. The brain and liver were removed and plasma was saved. The AGT mRNA significantly increased in the hypothalamus and liver in cold-treated rats from the first week of exposure to cold, and was maintained throughout the time of exposure to cold (n=4, p<0.01). The AGT protein levels in the brain, liver and plasma did not differ significantly between cold-treated and control rats (p>0.05, n=4). The hypothalamic Ang II levels were significantly increased, whereas plasma Ang II levels significantly decreased, in the rats of 5 weeks of cold exposure (n=8, p<0.05). Plasma ACE significantly increased in the rats of 1 week of cold exposure (p<0.05, n=12). The results show differential regulation of RAS components, AGT, ACE and Ang II, between brain and periphery in cold-exposed rats. We conclude that the exposure to low temperature initially increases plasma RAS but with continuous exposure to cold, the brain RAS maintains the hypertension, probably by sustained sympathetic activation, which would provide increased metabolism but also vasoconstriction leading to hypertension.