Blood vessels express estrogen receptors, but their role in cardiovascular physiology is not well understood. We show that vascular smooth muscle cells and blood vessels from estrogen receptor beta (ERbeta)-deficient mice exhibit multiple functional abnormalities. In wild-type mouse blood vessels, estrogen attenuates vasoconstriction by an ERbeta-mediated increase in inducible nitric oxide synthase expression. In contrast, estrogen augments vasoconstriction in blood vessels from ERbeta-deficient mice. Vascular smooth muscle cells isolated from ERbeta-deficient mice show multiple abnormalities of ion channel function. Furthermore, ERbeta-deficient mice develop sustained systolic and diastolic hypertension as they age. These data support an essential role for ERbeta in the regulation of vascular function and blood pressure.

contributed equally to this work Thyroid hormone, acting through several nuclear hormone receptors, plays important roles in thermogenesis, lipogenesis and maturation of the neonatal brain. The receptor specificity for mediating these effects is largely unknown, and to determine this we developed mice lacking the thyroid hormone receptor TRα1. The mice have an average heart rate 20% lower than that of control animals, both under normal conditions and after thyroid hormone stimulation. Electrocardiograms show that the mice also have prolonged QRS-and QT end -durations. The mice have a body temperature 0.5°C lower than normal and exhibit a mild hypothyroidism, whereas their overall behavior and reproduction are normal. The results identify specific and important roles for TRα1 in regulation of tightly controlled physiological functions, such as cardiac pacemaking, ventricular repolarisation and control of body temperature.

Mutations of mitochondrial DNA (mtDNA) cause several well-recognized human genetic syndromes with deficient oxidative phosphorylation and may also have a role in ageing and acquired diseases of old age. We report here that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy to manipulate the expression of the gene encoding mitochondrial transcription factor A (Tfam, previously named mtTFA), which regulates transcription and replication of mtDNA. Using a loxP-flanked Tfam allele (TfamloxP) in combination with a cre-recombinase transgene under control of the muscle creatinine kinase promoter, we have disrupted Tfam in heart and muscle. Mutant animals develop a mosaic cardiac-specific progressive respiratory chain deficiency, dilated cardiomyopathy, atrioventricular heart conduction blocks and die at 2-4 weeks of age. This animal model reproduces biochemical, morphological and physiological features of the dilated cardiomyopathy of Kearns-Sayre syndrome. Furthermore, our findings provide genetic evidence that the respiratory chain is critical for normal heart function.

Objective-Neutrophil gelatinase-associated lipocalin (NGAL) modulates the activity of matrix metalloproteinase (MMP) 9, an important mediator of vascular remodeling and plaque instability in atherosclerosis. This study aimed to analyze the expression of NGAL in atherosclerotic plaques and myocardial infarction (MI). Methods and Results-Atherosclerotic apolipoprotein E (apoE)Ϫ/Ϫ ϫ low-density lipoprotein receptor (LDLR) Ϫ/Ϫ and C57BL/6J control mice were exposed to brief hypoxic stress (10 minutes of 10% oxygen). Expression of the mouse NGAL homolog (24p3) and MMP-9 was analyzed 48 hours later by quantitative RT-PCR, immunohistochemistry, and zymography. Hypoxic stress increased NGAL/24p3 mRNA in the cardiac vasculature. NGAL/24p3 was also increased in atherosclerotic plaques of apolipoprotein E Ϫ/Ϫ ϫ LDLR Ϫ/Ϫ mice compared with C57BL/6J mice. Mice developing MI exhibited the highest plaque mRNA expression of NGAL/24p3 and MMP-9. Zymography revealed strong proteolytic activity in areas rich in 24p3 and MMP-9 protein. Immunohistochemistry performed on human carotid endarterectomy specimens and control tissue from the internal mammary artery showed colocalization of MMP-9 and NGAL with macrophages in the atherosclerotic plaques. Conclusions-NGAL/24p3 is increased in atherosclerotic plaques and MI. Colocalization with MMP-9 in areas with high-proteolytic activity suggests a role for NGAL/24p3 in modulating the MMP-9-mediated remodeling of plaques and infarcted hearts. Key Words: atherosclerosis Ⅲ myocardial infarction Ⅲ hypoxia Ⅲ matrix metalloproteinase Ⅲ remodeling C omplications to coronary atherosclerosis leading to myocardial infarction were previously believed to be because of the physical obstruction of the vessel lumen; however, 60% to 70% of myocardial infarctions (MIs) result from nonocclusive plaques. 1-4 Current evidence instead suggest that physical disruption of atherosclerotic plaques triggers thrombus formation, which may lead to MI. 5-7 The 2 major precipitating factors of thrombus formation are disruption of the plaque cap and erosion of its endothelial lining. Inflammation within the atherosclerotic plaque has been suggested to promote the progression toward plaque disruption by causing plaque instability. 8 Inflammatory mediators found in the atheroma have been shown to inhibit smooth muscle growth and collagen production and to augment matrix metalloproteinase (MMP) activity. 9 -12 This can result in decreased collagen content and weakening of plaque structure, leaving the fibrous cap prone to rupture.MMPs are a family of endopeptidases capable of degrading the molecular components of the extracellular matrix. They play important roles in a variety of pathological processes, such as atherosclerosis and tumor cell invasion. In particular, gelatinase B (MMP-9) is thought to be associated with diseases such as abdominal aortic aneurysm, atherosclerosis, and plaque rupture. 13 In cancer patients, urinary highmolecular weight MMPs have been shown to be independent predictors of metastatic cancers,...