Severe acute respiratory syndrome (SARS) was first identified in Guangdong Province in China (28). Over the ensuing 9 months, more than 8,000 cases were identified throughout the world, with a ϳ10% case fatality rate. A novel coronavirus, SARS coronavirus (SARS-CoV), was identified as the causative agent (6,17,29,32). Initial investigations indicated that the virus spread to humans from infected exotic animals such as Himalayan palm civets (Paguma larvata) and Chinese ferret badgers (Melogale moschata) (12); more recent work has suggested that the natural reservoirs for the virus are wild bat populations in China (19,24). Although SARS has not recurred in human populations to a significant extent since 2003, the potential severity of such a recurrence has spurred interest in developing an animal model for the human disease.SARS-CoV infects and replicates in mice, ferrets, hamsters, and several species of nonhuman primates (cynomolgus and rhesus macaques, African green monkeys, and common marmosets) (reviewed in reference 37). However, none of these animals develop a clinical disease that is reproducible and equivalent in severity to that observed in SARS patients. A mouse model would be useful for answering many questions about SARS pathogenesis and for testing vaccine efficacy, in part because reagents for the study of the immune response are widely available. However, other than aged or immunocompromised (STAT1 Ϫ/Ϫ ) mice (37), these animals do not develop significant clinical disease, and lethality has not been demonstrated in any murine model of SARS. With the goal of developing a more robust murine model, we generated transgenic (Tg) mice in which expression of hACE2 (human angiotensin-converting enzyme 2, the primary host cell receptor for SARS-CoV [23]) was targeted to epithelial cells. While human ACE2 and murine ACE2 (mACE2) molecules are very homologous, mACE2 does not support SARS-CoV binding as efficiently as hACE2 (22). Here we show that the transgenic expression of hACE2 in epithelia converts a mild SARS-CoV infection into a rapidly fatal disease. MATERIALS AND METHODSMice. All animal studies were approved by the University of Iowa and the Veterans Administration Institutional Animal Care and Use committees. Mice transgenic for expression of hACE2 (K18-hACE2 mice) were generated as follows (see Fig. 1A). The hACE2 coding sequence was PCR amplified from IMAGE consortium clone ID 5243048 (ATCC, Manassas, VA) and cloned into the pCR2.1-TOPO vector (Invitrogen, Carlsbad, CA). The lacZ coding sequence in the previously described pK18mTElacZ-K18i6x7pA construct (16) (a kind gift from Jim Hu, Hospital for Sick Children, Toronto, Canada) was then replaced by the hACE2 coding sequence to create pK18-hACE2. 5Ј of the hACE2 coding sequence, this plasmid contains 2.5 kb of upstream genomic sequence, the promoter, and the first intron (with a mutation in the 3Ј splice acceptor site to reduce exon skipping) of the human cytokeratin 18 (K18) gene as well as a translational enhancer sequence from alfalfa mosaic vi...

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that plays a critical role in metabolism. Thiazolidinediones, high-affinity PPARgamma ligands used clinically to treat type II diabetes, have been reported to lower blood pressure and provide other cardiovascular benefits. Some mutations in PPARgamma (PPARG) cause type II diabetes and severe hypertension. Here we tested the hypothesis that PPARgamma in vascular muscle plays a role in the regulation of vascular tone and blood pressure. Transgenic mice expressing dominant-negative mutations in PPARgamma under the control of a smooth-muscle-specific promoter exhibit a loss of responsiveness to nitric oxide and striking alterations in contractility in the aorta, hypertrophy and inward remodeling in the cerebral microcirculation, and systolic hypertension. These results identify PPARgamma as pivotal in vascular muscle as a regulator of vascular structure, vascular function, and blood pressure, potentially explaining some of the cardioprotective effects of thiazolidinediones.

T he renin-angiotensin system (RAS) is well known for its physiological and pathophysiological roles in the regulation of blood pressure (BP) and cardiovascular function. 1,2 A new component of the RAS, angiotensin-converting enzyme (ACE) type 2 has been identified, from human heart failure ventricle and lymphoma cDNA libraries (reviewed elsewhere 3,4 ). Although the angiotensin-converting enzyme type 2 (ACE2) transcript was first described in heart, kidney and testis, additional studies reported ACE2 mRNA in rat medulla oblongata 4 and ACE2 activity in mouse brain. 5 Recently, we showed the presence of both ACE2 protein and mRNA widespread throughout the murine brain, in regions involved in the central regulation of cardiovascular function as well as noncardiovascular regions. 6 ACE2 converts Ang II into the vasodilatory peptide Ang-(1-7) with an affinity 400-fold higher than for Ang I. 7 In the central nervous system (CNS), Ang-(1-7) has been shown to enhance sensitivity of the bradycardic component of the cardiac baroreceptor reflex 8 and to promote vasodilation in hypertensive animals. 9,10 As a key enzyme in generating Ang-(1-7), ACE2 is thought to be a pivotal player in central BP regulation. 3,5 Several evidences from various laboratories have shown the beneficial effects of peripheral ACE2 in the regulation of cardiovascular hypertrophy and BP control. 10 -12 In the CNS, using a lentivirus coding for ACE2, Yamazato et al previously showed that ACE2 overexpression in the rostral ventrolateral medulla, could reverse hypertension in spontaneously hypertensive rats (SHR). 13 More recently, we reported that brain-targeted ACE2 overexpression in the subfornical organ (SFO) prevents the acute Ang II-mediated pressor and Original