IntroductionIn vitro studies have demonstrated that angiotensin (Ang) II directly stimulates vascular smooth muscle cell (VSMC) The pathogenesis of vascular diseases such as hypertension, atherosclerosis, and restenosis involves a process of vascular remodeling associated with increased local expression of biologically active substances that are postulated to play pathophysiological roles. In hypertension, the arteries undergo a process of vascular hypertrophy that is associated with the activation of a local angiotensin system (1-3). The potential role of autocrine/paracrine mediators such as angiotensin in vascular pathobiology independent from systemic factors has been suggested from indirect evidence, that is, cell culture studies, morphologic analysis, and/or by systemic administration of antagonists and agonists (1-16). To elucidate the role of a specific autocrine/paracrine factor, we have developed an efficient in vivo gene transfer technique to examine the consequences of overexpression of the factor in a segment of the carotid artery in the intact rat. This approach is particularly powerful because the locally transfected vessel segment can be compared with adjacent untransfected segments as well as the contralateral vessel. Furthermore, the transfected segment is exposed to the same blood pressure and circulating factors as the control vessel. In this study, we examined the role of autocrine/paracrine angiotensin as a mediator of vascular hypertrophy in vivo. Previous data have demonstrated that angiotensin II (Ang II)' can stimulate smooth muscle cell growth and modulate extracellular matrix (10-13). Ang II is generated via an enzymatic cascade in which tissue angiotensin converting enzyme (ACE) plays a key role (17)(18)(19)

Cardiac fibroblasts, as the source of extracellular matrix for the left ventricle, subserve important functions to cardiac remodeling and fibrotic development following myocardial infarction or with pressure-overload cardiac hypertrophy. The fibroblast may be the target cell for angiotensin-converting enzyme inhibitors (ACEI) that are cardioprotective and reverse collagen deposition and remodeling but whose mechanisms of action remain controversial. Because we previously documented phenotypic differences between cardiac fibroblasts from the spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) left ventricle, the present study evaluated whether phenotypic differences also exist in the release of endogenous arachidonic acid metabolites or in the activation of phospholipase D, and the importance of observed differences to the formation of collagen and the mechanism of action of ACEI. The experimental design compared endogenous sources of arachidonic acid with exogenous prelabeling of cells. Angiotensin II stimulated greater arachidonic acid release than bradykinin, and WKY cells were more responsive than SHR. The major prostanoid formed by cardiac fibroblasts was prostaglandin I2 (PGI2), with more prostacyclin production by WKY cells than SHR cells both under nonstimulated conditions and in response to angiotensin II or bradykinin. Beraprost, a PGI2 analogue, was shown to decrease growth rate and DNA synthesis of fibroblasts and to inhibit mRNA expression for collagen types I and III, with SHR cells being less responsive to beraprost than WKY cells. These results potentially implicate eicosanoid metabolism, particularly PGI2, in collagen formation, fibrotic development, and cardiac remodeling, and they imply that the SHR genetic hypertension model may be predisposed to excess cardiac fibrosis.

Abstract-Cardiac fibrosis after myocardial infarction and in chronic hypertension involves an increase in the synthesis and deposition of collagen within the myocardium. Angiotensin-converting enzyme (ACE) inhibitors limit hypertrophy and fibrosis; their mechanism of action remains controversial, although kinins have been implicated to play a role. Because both bradykinin and prostaglandins (PG) have been shown to reduce collagen gene expression in cardiac fibroblasts, the goal of this study was to determine whether the bradykinin effect was mediated through enhanced prostaglandin formation by cardiac fibroblasts. Bradykinin increased [ 3 H]arachidonic acid metabolite release 2.3-fold over control and stimulated a dose-dependent increase in 6-keto PGF 1␣ (the stable metabolite of PGI 2 ) release from these cells, in which 1 nmol/L bradykinin produced a 4-fold increase in 6-keto PGF 1␣ release. Beraprost (a PGI 2 analogue) reduced steady-state pro␣1(I) and pro␣1(III) collagen mRNA levels by 35.6Ϯ6.6% and 34.2Ϯ10.0%, respectively. Bradykinininduced reductions in collagen type I and III gene expression were reversed by pretreatment with indomethacin. Our results indicate that one mechanism by which bradykinin modulates collagen biosynthesis via the rabbit cardiac fibroblast involves formation of arachidonic acid metabolites, particularly PGI 2 . The results of the present study argue that stabilization of endogenous kinins (as by ACE inhibitors) would enhance prostacyclin production and result in the attenuation of collagen gene expression, with potential implications for collagen synthesis and deposition within the myocardium. (Hypertension. 1998;32:84-88.) Key Words: bradykinin Ⅲ collagen Ⅲ prostaglandins Ⅲ fibroblasts Ⅲ rabbits A fter myocardial infarction and in chronic hypertension, the collagen content of the LV is increased. ACE inhibitors have been shown to be efficacious in the treatment of patients with these pathologies and to improve survival. [1][2][3] Furthermore, in animal studies, one consequence of the use of ACE inhibitors after coronary artery ligation or aortic banding is a reduction in LV hypertrophy 4,5 and collagen content of the myocardium. [6][7][8][9] This attenuation in collagen deposition and LV mass is blunted by coadministration of a BK receptor antagonist, 7,10,11 implying a role for the kinin system in regulating LV remodeling. Because ventricular remodeling involves both hypertrophic growth of myocytes and increases in interstitial fibrosis, ACE inhibitors potentially may alter either or both components. In recent studies from our laboratory and others, BK has been reported to reduce collagen gene expression via cardiac fibroblasts, 12,13 but the signaling pathways involved in BK-induced modulation of collagen expression have not been fully explored.Kinins stimulate the release of AA metabolites, including prostaglandins and prostanoids from a variety of cell types 14 -18 20 However, BK-induced stimulation of prostaglandin formation has not been fully examined as a primary mechan...

This paper proposes a new algorithm to determine the wave turbopause based on numerical differentiation using temperature data collected from the Sounding of the Atmosphere using Broadband Emission Radiometry onboard the Thermosphere Ionosphere Mesosphere Energetics Dynamics satellite. The vertical gradient profile of the temperature standard deviation, which serves as a proxy of wave activity, is obtained based on Tikhonov regularization. In the vicinity of the altitude of wave turbopause, wave damping is much reduced, and upward wave propagation occurs with little damping effect. The corresponding vertical gradient profile should reach a maximum with values that are no longer negative. Thus, we determine the wave turbopause as the unique maximum that is the first after the last change in the derivative value from negative to positive. The wave turbopause altitudes determined by this new method agree well with those of previous studies, especially regarding the behavior of the monthly variation. The error of the wave turbopause altitude derived from this new method is 1.9 km, which is much improved from the error of 3.3 km estimated by the previous method. Additionally, latitudinal variations of the wave turbopause altitude for different seasons and their monthly variations for 0°, 30°N, and 70°N latitudes during 2016–2018 are presented. Similar to the mesopause, the wave turbopause also exhibits a two‐level structure with a summer minimum at high latitudes.

We established an efficient and nontoxic in vivo gene transfer method mediated by the Sendai virus (hemagglutinating virus of Japan [HVJ]), liposomes, and nuclear protein. In this study, to produce a hypertensive model rat that is dependent on human renin, the human renin gene was introduced into adult rat liver by our efficient in vivo gene transfer method using HVJ and liposomes (HVJ-liposomes). The rats treated with HVJ-liposomes containing the human renin gene showed a significant elevation of blood pressure for 6 days compared with control rats, which received injections of HVJ-liposomes without the human renin gene. On day 5 after the transfer, human active renin as well as angiotensin II were found in the plasma of rats in which the human renin gene was introduced. Moreover, the blood pressure of these rats was significantly correlated with the plasma levels of human active renin and angiotensin II. To confirm that the elevated blood pressure was due to the expression of the human renin gene, we administered a newly developed specific human renin inhibitor, FK 906. The elevated blood pressure was normalized by the intravenous administration of this drug. These data indicate that this hypertensive rat was produced by the in vivo transfer of the human renin gene into rat liver and that the expressed human renin cleaved rat substrate (angiotensinogen). This hypertensive rat produced by in vivo gene transfer should be useful in further studies on hypertension.