The relation between intra-abdominal visceral fat accumulation and blood pressure was investigated in 67 obese women (mean body mass index, 33.6±3.1; average age, 50±ll years). As an index of intra-abdominal fat accumulation, the ratio of the intra-abdominal visceral fat area to subcutaneous fat area was determined using a computed tomographic section at the level of the umbilicus. When the obese subjects were divided into a hypertensive group and a normotensive group, the ratio of the intra-abdominal visceral fat area to subcutaneous fat area in the hypertensive group was significantly higher (0.53±0.33 versus 0.29±0.12, p<0.01). Significant correlations between the ratio of intra-abdominal visceral fat area to subcutaneous fat area and systolic blood pressure (r=0.62, p< 0.001) and diastolic blood pressure (r=0.53, p< 0.001) also were found. However, no significant difference existed in either the body mass index or the waist-to-hip circumference ratio between the hypertensive and normotensive groups. Plasma renin activity, aldosterone, epinephrine, and norepinephrine levels were not significantly different between the two groups. Moreover, the correlation between the ratio of the intra-abdominal visceral fat area to subcutaneous fat area ratio and blood pressure was found independent of age and body mass index by multiple regression analyses. We conclude that intra-abdominal fat accumulation itself may play an important role in the pathogenesis of hypertension in obesity. (Hypertension 1990;16:484-490) I t has been noted that the incidence of circulatory and metabolic complications among comparably obese subjects differs depending on their body habitus.1 We have developed a method to estimate fat distribution using computed tomography (CT) scan, which clearly distinguishes between subcutaneous fat and intra-abdominal visceral fat 2 and have demonstrated a close correlation between intra-abdominal fat accumulation and metabolic disturbances.3 Further, using this method we reported that the accumulation of intra-abdominal visceral fat itself may reflect cardiac dysfunction and metabolic disorders better than subcutaneous fat. 4 -7 Therefore, we propose the existence of two types of obesity: visceral fat obesity, characterized by a pronounced accumulation of fat in the abdominal cavity, and subcutaneous fat obesity, From The Second Department of Internal Medicine, Osaka University Medical School, Fukushima-ku, Osaka, Japan.Presented in part at the 62nd Annual Scientific Sessions of the American Heart Association, New Orleans, Louisiana, November [13][14][15][16] 1989.Address for correspondence: Hideyuki Kanai, MD, The Second Department of Internal Medicine, Osaka University Medical School, 1-1-50 Fukushima, Fukushima-ku, Osaka 553, Japan.Received March 7,199O, accepted in revised form June 15,1990. characterized by an accumulation mainly in the subcutis (Figure 1). We also reported 8 that this classification is more useful than other classifications of fat distribution, 9 "16 including the waist-to-hip circum...

Objective-Myocardin is a coactivator of serum response factor (SRF) required for vascular smooth muscle cell (VSMC) differentiation. HERP1 is a transcriptional repressor, which is abundantly expressed in vascular system and is known to function as a target gene of Notch. However, the role of HERP1 in the pathogenesis of vascular lesions remains unknown. The present study characterizes the expression of HERP1 in normal and diseased vessels, and tests the hypothesis that HERP1 inhibits SRF/myocardin-dependent SMC gene expression. Methods and Results-Immunohistochemistry revealed that HERP1 and myocardin expression was localized to SMC in the neointima of balloon-injured rat aorta and in human coronary atherosclerotic lesions. Expression of both HERP1 and myocardin was elevated in cultured VSMCs compared with medial SMC. Overexpressed HERP1 inhibited the myocardin-induced SMC marker gene expression in 10T1/2 cells. HERP1 protein interfered with the SRF/CArG-box interaction in vivo and in vitro. Immunoprecipitation assays showed that HERP1 physically interacts with SRF. Conclusions-HERP1 expression was associated with the SMC proliferation and dedifferentiation in vitro and in vivo.HERP1 may play a role in promoting the phenotypic modulation of VSMCs during vascular injury and atherosclerotic process by interfering with SRF binding to CArG-box through physical association between HERP1 and SRF. Key Words: HERP1 Ⅲ myocardin Ⅲ serum response factor Ⅲ smooth muscle cells P henotypic modulation of vascular smooth muscle cells (VSMCs) from contractile to synthetic forms plays a pivotal role in the pathogenesis of vascular diseases including atherosclerosis and restenosis after angioplasty. 1 It is wellestablished that VSMC phenotype is regulated by a complex array of local environmental cues including humoral factors, cell-cell and cell-matrix interactions, inflammatory stimuli, and mechanical stresses. Such complex stimuli downregulate a number of genes required for the contractile phenotype in synthetic VSMCs. These include smooth muscle myosin heavy chain (SM-MHC), SM22␣, caldesmon, and calponin. Because the genes encoding these proteins are differentially expressed depending on the proliferative state of VSMCs, transcription factors regulated by numerous stimuli are responsible at least in part for the distinct pattern of gene expression seen in synthetic VSMCs.There is mounting evidence that most SMC marker proteins such as SM-MHC and SM22␣ are controlled by serum response factor (SRF), which binds to a sequence known as a CArG box and recruits a potent coactivator, myocardin, for SMC differentiation. 1 When myocardin is ectopically expressed in nonmuscle cells, it can induce SMC differentiation. 2,3 Most importantly, mouse embryos deficient for myocardin show no evidence of vascular SMC, indicating myocardin as a necessary and sufficient factor for SMC differentiation in vivo. 4 These observations, in conjunction with downregulation of SMC marker genes in synthetic VSMC, led us to speculate that myocardin express...

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Induction of HIF-1alpha protein and PAI-1 gene expression in response to hypoxia was regulated by ROS production and c-Src activation in vascular smooth muscle cells. Mitochondria linked the hypoxic signal to c-Src, which in turn led to HIF-1alpha protein and PAI-1 gene expression. These results provide evidence that hypoxia induces the ROS-mediated and c-Src-dependent signaling cascades which are closely associated with angiogenesis and thrombosis in atherosclerotic vasculature.

Abstract-Transforming growth factor (TGF)-␤ plays a major role in the development of vascular diseases. Despite the pleiotropic effects of TGF-␤ on vascular smooth muscle cells (VSMCs), only a few genes have been characterized as direct targets of TGF-␤ in VSMCs. Cardiac ankyrin repeat protein (CARP) has been thought to be expressed exclusively in the heart. In the present study, we showed that CARP is expressed in the vasculature after balloon injury and in cultured VSMCs in response to TGF-␤. Analysis of a half-life of the cytoplasmic CARP mRNA levels and the transient transfection of the CARP promoter/luciferase gene indicates that the regulation of CARP expression is increased by TGF-␤ at the transcriptional level. Transfection of expression vectors encoding Smads significantly activated the CARP promoter/luciferase activity. Deletion analysis and site-specific mutagenesis of the CARP promoter indicate that TGF-␤ response element is localized to CAGA motif at Ϫ108 bp relative to the transcription start site. Electrophoretic mobility shift assays showed that the binding activity to the CAGA motif was increased in nuclear extracts of cultured VSMCs by TGF-␤. Cells transfected with adenovirus vector expressing CARP showed a significant decrease in DNA synthesis.

Objective-Transforming growth factor-␤1 (TGF␤1) and fibroblast growth factor (FGF) families play a pivotal role during vascular development and in the pathogenesis of vascular disease. However, the interaction of intracellular signaling evoked by each of these growth factors is not well understood. The present study was undertaken to examine the molecular mechanisms that mediate the effects of TGF␤1 and basic FGF (bFGF) on smooth muscle cell (SMC) gene expression. Methods and Results-TGF␤1 induction of SMC gene expression, including smooth muscle protein 22-␣ (SM22␣) and smooth muscle ␣-actin, was examined in the pluripotent 10T1/2 cells. Marked increase in these mRNA levels by TGF␤1 was inhibited by c-Src-tyrosine kinase inhibitors and protein synthesis inhibitor cycloheximide. Functional studies with deletion and site-directed mutation analysis of the SM22␣ promoter demonstrated that TGF␤1 activated the SM22␣ promoter through a CC(A/T-rich) 6 GG (CArG) box, which serves as a serum response factor (SRF)-binding site. TGF␤1 increased SRF expression through an increase in transcription of the SRF gene. In the presence of bFGF, TGF␤1 induction of SMC marker gene expression was significantly attenuated. Transient transfection assays showed that bFGF significantly suppressed induction of the SM22␣ promoter-driven luciferase activity by TGF␤1, whereas bFGF had no effects on the TGF␤1-mediated increase in SRF expression and SRF:DNA binding activity. Mitogen-activated protein kinase kinase-1 (MEK1) inhibitor PD98059 abrogated the bFGF-mediated suppression of TGF␤1-induced SMC gene expression. Key Words: basic fibroblast growth factor Ⅲ transforming growth factor-␤1 Ⅲ serum response factor Ⅲ SM22␣ Ⅲ smooth muscle cells P henotypic modulation of smooth muscle cells (SMCs) contributes to development of atherosclerotic and restenotic lesions. There is considerable interest in identifying the various extracellular signals that regulate SMC phenotype and the molecular mechanisms underlying such SMC plasticity. Transforming growth factor-␤1 (TGF␤1) is one of the primary differentiation factors for SMCs. 1 TGF␤1 upregulates several SMC differentiation markers, such as smooth muscle ␣-actin (SM␣-actin), smooth muscle myosin heavy chain, SM22␣, and h1 calponin in vitro. Moreover, TGF␤1 induces expression of these SMC differentiation maker genes in a variety of nonsmooth muscle precursor cell types in culture, including multipotent embryonic fibroblast (10T1/2 cells) and neural crest cells. 2,3 These results suggest that TGF␤1 evokes an important signal that induces SMC differentiation. Conclusion-OurIn contrast, basic fibroblast growth factor (bFGF) is one of the most important mitogenic growth factors for SMCs 1 and plays an important role in the onset and development of vascular disease. Several studies indicated that experimental reduction in bFGF expression inhibits SMC proliferation after intimal injury. Lindner et al suggested that in injured arteries, bFGF and FGF receptor-type 1 may be involved in the continued prolifer...

Low BMI, eGFR, CLI, and diabetes are significant risk factors for mortality in PAD. The obesity paradox was verified and may be partly explained by low BMI mediated by malnutrition and systemic inflammation due to PAD or chronic obstructive pulmonary disease.

We investigated the relationship between changes in blood pressure and fat distribution after a 12-week low-calorie diet in 26 obese hypertensive women whose average age was 50 +/- 13 years, mean body mass index was 33.7 +/- 3.1 kg/m2, and mean blood pressure was 112 +/- 9 mm Hg. As an index of intra-abdominal fat accumulation, we used the ratio of the intra-abdominal visceral fat area to subcutaneous fat area, determined by a computed tomographic section at the level of the umbilicus. Subjects lost a mean of 9.4 +/- 4.1 kg on a 1200-kcal (5040-kJ) diet for 12 weeks. Their mean blood pressure fell from 112 +/- 9 to 101 +/- 12 mm Hg (P < .001). The ratio of the visceral to subcutaneous fat area was significantly reduced after weight reduction from 0.56 +/- 0.33 to 0.45 +/- 0.27 (P < .02). Fasting plasma glucose and plasma glucose area after a 75-g oral glucose tolerance test also were significantly reduced by weight reduction. The change in mean blood pressure after weight reduction was not correlated with the change in body weight or body mass index but was correlated with the reduction in visceral fat area or ratio of visceral fat to subcutaneous fat area. Changes in mean blood pressure also were correlated with changes in fasting plasma glucose levels and the plasma glucose area determined by 75-g oral glucose tolerance test. Results indicate that a decrease in intra-abdominal visceral fat, rather than simply of body weight, may reduce blood pressure in obese hypertensive subjects. The mechanism may involve an improvement in glucose tolerance caused by weight reduction.