Abstract-Cardiac fibroblasts (CFs) produce extracellular matrix proteins and participate in the remodeling of the heart.It is unknown if brain natriuretic peptide (BNP) is synthesized by CFs and if BNP participates in the regulation of extracellular matrix turnover. In this study, we examined the production of BNP in adult canine CFs and the role of BNP and its signaling system on collagen synthesis and on the activation of matrix metalloproteinases (MMPs Key Words: cardiac fibroblasts Ⅲ extracellular matrix Ⅲ remodeling Ⅲ cGMP Ⅲ protein kinase G T he cardiac interstitium is a dynamic structure, as reflected by continuous synthesis and degradation of matrix proteins. The family of matrix metalloproteinases (MMPs) consists of more than 20 different zinc-containing, Ca 2ϩ -dependent endopeptidases. 1,2 They degrade matrix proteins and therefore play an important role in the physiological regulation of the interstitium. The interstitial collagenases (MMP-1 and MMP-13), the stromelysin (MMP-3), the gelatinases (MMP-2 and MMP-9), and membranous-type 1 MMPs (MMP-14; MT1-MMP) have been demonstrated within the mammalian myocardium. 2 Furthermore, dysregulation of MMP proteins and their endogenous inhibitor, tissue inhibitors of MMP (TIMP), has been observed in the hypertensive and the failing heart, suggesting an important role of MMP in the process of ventricular remodeling. [3][4][5][6][7] Cardiac fibroblasts (CFs) play a crucial role in the regulation of the extracellular matrix (ECM) of the heart by synthesizing collagen and other matrix proteins as well as promoting their degradation by secreting MMP proteins. In response to myocardial injury, activation of CFs occurs. These activated CFs (myofibroblasts) have special morphological and functional characteristics. 8,9 The natriuretic peptides (NPs) atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) play important roles in maintaining cardiorenal homeostasis under physiological and pathological conditions. 10 ANP and BNP are synthesized by cardiomyocytes, and their production is stimulated in pathologic conditions such as myocardial infarction (MI), cardiac hypertrophy, and heart failure (HF). 11-13 ANP and BNP have natriuretic, vasodilating, and lusitropic properties, and they inhibit the sympathetic and renin-angiotensin-aldosterone system. 14,15 These actions are primarily mediated by the second messenger cGMP. 16 Cameron et al 17 have recently reported that ANP is produced in CFs after MI, indicating that fibroblasts, like cardiomyocytes, can be a source of NPs. However, it remains unknown if BNP is produced by CFs.Although it is well established that BNP has growthinhibiting properties in the heart, 18 -21 the role of BNP on the regulation of the cardiac interstitium remains undefined. Given the widespread cross-talk of the NPs with other systems that are activated in cardiorenal disorders, we aimed to investigate whether CFs are a source of BNP and whether BNP and its signaling system contribute to the regulation of Original

Abstract-Abdominal aortic aneurysm (AAA) is histologically characterized by medial degeneration and various degrees of chronic adventitial inflammation, although the mechanisms for progression of aneurysm are poorly understood. In the present study, we carried out histological study of AAA tissues of patients, and interventional animal and cell culture experiments to investigate a role of mast cells in the pathogenesis of AAA. The number of mast cells was found to increase in the outer media or adventitia of human AAA, showing a positive correlation between the cell number and the AAA diameter. Aneurysmal dilatation of the aorta was seen in the control (ϩ/ϩ) rats following periaortic application of calcium chloride (CaCl 2 ) treatment but not in the mast cell-deficient mutant Ws/Ws rats. The AAA formation was accompanied by accumulation of mast cells, T lymphocytes and by activated matrix metalloproteinase 9, reduced elastin levels and augmented angiogenesis in the aortic tissue, but these changes were much less in the Ws/Ws rats than in the controls. Similarly, mast cells were accumulated and activated at the adventitia of aneurysmal aorta in the apolipoprotein E-deficient mice. The pharmacological intervention with the tranilast, an inhibitor of mast cell degranulation, attenuated AAA development in these rodent models. In the cell culture experiment, a mast cell directly augmented matrix metalloproteinase 9 activity produced by the monocyte/macrophage. Collectively, these data suggest that adventitial mast cells play a critical role in the progression of AAA. Key Words: adventitia Ⅲ inflammation Ⅲ mast cell Ⅲ matrix metalloproteinase Ⅲ aneurysm A bdominal aortic aneurysm (AAA), a relatively common disorder among elderly people, is pathologically characterized by atherosclerosis of the intima and disruption or attenuation of the elastic media with various degrees of adventitial inflammatory infiltration. 1,2 Because approximately 4% of adults older than 65 years harbor AAA, it is among the leading 15 causes of death in elderly persons in the United States. 3 Although substantial efforts have been made to clarify the mechanism of development of AAA, there is currently no effective method to inhibit enlargement of AAA. Repair surgery is necessary to prevent rupture in patients with progressively enlarging AAA, whereas the operative risk is often relatively high because of the other complications resulting from aging.Recent reports suggest that chronic inflammation of the aortic wall and progressive degradation of extracellular matrix proteins are involved in the development, progression, or rupture of AAA. 2,4 -8 As a component of the immune system, mast cells play a critical role in defending hosts against pathogens by releasing a number of immunoregulatory mediators. 9 These cells have also been shown to initiate the inflammatory response by releasing proinflammatory cytokines, growth factors, angiogenic mediators, and proteases, 10 as well as by recruiting other inflammatory cells, such as neutrophils, macrop...

Abstract-Adrenomedulhn(AM), a potent vasodllator peptlde, exists m the cardiac ventricle, however, the role of AM m the ventricular tissue remams unknownIn the present study, we mvestlgated the production and secretlon of AM m cultured neonatal rat cardlomyocytes, and we exammed the effect of AM on de novo protein synthesis m these cells by measurmg ['4C] any efforts have been made to clarify the mechanisms of growth regulation of the cardiac myocardmm because of comphcatlons of the heart caused by cardiac hypertrophy At the cellular level, cardiac myocytes are known to compensate for increased workload by an Increase m their size but not m their number because these cell? are unable to dlvlde later m life ' Multiple factors such as hemodynamlc overload and humoral factors were shown to be mvolved m the process of the cardiac hypertrophy,2-4 but the detailed mechanism remams to be elucidated AM, a potent vasodllator peptlde first detected m human pheochromocytoma, has slight homology with CGRP' In addltlon to the direct vasodllator actlvlty, AM has been shown to possess a broad spectrum of blologlcal actions such as dluresls, mhlbltlon of aldosterone secretion, and mhlbltlon of prohferatlon of vascular smooth muscle cells '-* A specific RIA revealed that AM circulates m the blood and 1s present m the adrenal medulla, kidney, lung and cardiac ventricle of humans and rats ')I" The plasma AM concentration m patients with essential hypertension or primary aldosteromsm was reported to be higher than that m normotenslve control subjects, suggesting a possible role of AM m acting against further elevation of blood pressure "J' In the cardiac ventricle, AM mRNA 1s expressed at a level comparable to that of the adrenal medulla,'3b'4 and both the AM content and mRNA expression are increased m Dahl salt-sensmve and renovascular hypertensive rats compared to respective controls I516 However, at present, It remains unknown whether the cardiac myocytes secrete AM, and what the role of AM 1s m the cardiac tissueIn the first part of this study, we exammed the production and secretion of AM from cultured neonatal cardiac myocytes In the second, we investigated the effect ofAM on the de novo protein synthesis m these cells by measurmg ['4C]phenylalanme mcorporatlon, and we evaluated the action of endogenous AM by using a peptlde analogue of CGRP and anti-AM monoclonai antibody Chemicals Methods Ang II, rat AM, human

Regulation of the extracellular matrix (ECM) is an important therapeutic target that can potentially attenuate the adverse ventricular remodeling seen in the progression of heart failure. Matrix metalloproteinases (MMPs) degrade numerous ECM proteins. Importantly, the activation of MMPs and their endogenous inhibitors (TIMPs) are associated with ventricular remodeling. Bioactive-molecules (vasoactive peptides) become activated in proportion to the magnitude of heart failure and have been demonstrated to affect directly collagen degradation as well as collagen synthesis in the myocardium. Pro-fibrotic factors such as norepinephrine, angiotensin II, and endothelin-1 stimulate fibrosis by modulating collagen synthesis and MMP/TIMP activity. Antagonism of these bioactive-molecules has produced improved hemodynamic performance concomitant with modulation of MMP/TIMP activity and in association with reverse remodeling. The natriuretic peptides and nitric oxide, both of which function via the second messenger cGMP, demonstrate anti-fibrotic actions by inhibiting collagen synthesis and by stimulating MMP activity. Furthermore, bioactive-molecules along with certain cytokines are reported to amplify MMP activity, suggesting that different signaling systems work together to modulate ECM turnover. Taken together, the evidence supports an important functional role for bioactive-molecules in the regulation of ECM turnover and suggests that pharmacological intervention at the level of such bioactive molecules may provide potential therapeutic strategies for attenuation of the adverse ventricular remodeling associated with the progression of heart failure.

Background-BAY 41-2272 is a recently introduced novel orally available agent that directly stimulates soluble guanylate cyclase (sGC) and sensitizes it to its physiological stimulator, nitric oxide. To date, its therapeutic actions in congestive heart failure (CHF) remain undefined. We characterized the cardiorenal actions of intravenous BAY 41-2272 in a canine model of CHF and compared it to nitroglycerin (NTG). Methods and Results-CHF was induced by rapid ventricular pacing for 10 days. Cardiorenal and humoral function were assessed at baseline and with administration of 2 doses of BAY 41-2272 (2 and 10 g · kg Ϫ1 · min Ϫ1 ; nϭ8) or NTG (1 and 5 g · kg Ϫ1 · min