摘要:

Abstract—In this study, we used the somatic gene delivery approach to explore the role of the kallikrein-kinin system (KKS) in cardiac remodeling and apoptosis after myocardial infarction (MI). Rats were subjected to coronary artery ligation to induce MI, and adenovirus carrying the human tissue kallikrein or luciferase gene was injected into the tail vein at 1 week after surgery. Cardiac output gradually decreased from 2 to 6 weeks after MI, whereas delivery of the kallikrein gene prevented this decrease. Cardiac responses to dobutamine-induced stress were improved in rats receiving kallikrein gene as compared with rats receiving control virus at 6 weeks after MI. Kallikrein significantly improved cardiac remodeling by decreasing collagen density, cardiomyocyte size, and left ventricular internal perimeter and increasing capillary density in the heart at 6 weeks after MI. Kallikrein gene transfer attenuated myocardial apoptosis, which was positively correlated with remodeling parameters in the heart at 2 weeks after MI. Endothelial dysfunction, characterized by increased vascular resistance, decreased left ventricular blood flow, and decreased cardiac nitric oxide levels, existed in remodeled hearts at 2 weeks after MI, whereas kallikrein gene transfer improved these parameters. Kallikrein gene delivery improved cell survival parameters as shown by increased phospho-Akt and reduced caspase-3 activation at 2 weeks after MI. This study indicates that the kallikrein-kinin system plays an important role in preventing the progression of heart failure by attenuating cardiac hypertrophy and fibrosis, improving endothelial function, and inhibiting myocardial apoptosis through the Akt-mediated signaling pathway.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—The Gq-coupled receptor-signaling pathway has been implicated in the cardiac hypertrophic response to stress, but little is actually known about the contributions of Gq signaling in either the heart or the vasculature. Therefore, we developed a line of transgenic mice that express a peptide inhibitor of Gq (GqI) in vascular smooth muscle to determine if vascular Gq signaling was important in the cardiac hypertrophic response. After chronic administration of the Gq agonists phenylephrine, serotonin, and angiotensin II, we observed an attenuation of mean arterial blood pressure and an inhibition of cardiac hypertrophy in the transgenic mice with vascular-specific GqI expression. In contrast, cardiac GqI peptide expression did not attenuate the hypertension or the cardiac hypertrophy. Importantly, all mice were capable of cardiac hypertrophy, because direct &bgr;-adrenergic receptor stimulation induced a similar level of hypertrophy in both lines of transgenic mice. This clearly suggests that after chronic Gq-coupled receptor agonist administration, it is the hypertensive state induced by vascular Gq activation that mediates remodeling of the heart, rather than direct stimulation of cardiac Gq-coupled receptors. Thus, the contribution of vascular Gq-coupled signaling to the development of cardiac hypertrophy is significant and suggests that expression of the GqI peptide is a novel therapeutic strategy to lower Gq-mediated hypertension and cardiac hypertrophy.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Short-term administration of adrenomedullin, a recently discovered peptide with potent vasodilator, natriuretic, and aldosterone-inhibitory actions, has beneficial effects in experimental and clinical heart failure. The effects of prolonged adrenomedullin administration have not previously been assessed in this setting. Consequently, in 16 sheep with pacing-induced heart failure, we infused either adrenomedullin (10 ng/kg per minute; n=8) or a vehicle control (Hemaccel; n=8) for 4 days. Compared with control data, infusion of adrenomedullin persistently increased circulating levels of the peptide (by ≈9.5 pmol/L;P<0.001), in association with prompt (15 minutes) and sustained (4 days) increases in cardiac output (day 4, 27%), and reductions in peripheral resistance (30%), mean arterial pressure (13%), and left atrial pressure (24%; all,P<0.001). Adrenomedullin also significantly enhanced urinary sodium excretion (day 4, 3-fold;P<0.05), creatinine excretion (1.2-fold;P<0.001), and creatinine clearance (1.4-fold;P<0.001) over the 4 days of treatment, whereas urine volume and cAMP excretion tended to be elevated (both, 0.1>P>0.05). Plasma renin activity was increased (P<0.05), whereas aldosterone levels were reduced in a sustained fashion (P<0.01). Plasma endothelin rose transiently (hours 1 to 6) after initiation of treatment (P<0.05). Despite substantial cardiac unloading, plasma concentrations of the natriuretic peptides were not significantly different from control. In conclusion, long-term administration of adrenomedullin induces pronounced and sustained cardiovascular and renal effects in experimental heart failure, including reductions in cardiac preload and afterload, as well as augmentation of cardiac output, sodium excretion, and glomerular filtration. These findings support the concept of adrenomedullin as a protective hormone during hemodynamic compromise with therapeutic potential in heart failure.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—The study of left ventricular (LV) hypertrophy is hindered by problems with LV mass measurement by echocardiography. Both the M-mode and 2D area-length formulas for calculating LV mass assume a fixed geometric shape, which may be a source of error. We examined this hypothesis by using cardiovascular magnetic resonance images to eliminate the confounding effects of acoustic access and image quality. LV mass was measured directly in 212 healthy subjects by means of a standard 3D cardiovascular magnetic resonance technique. LV mass was also calculated by using the cube-function and area-length formulas with measurements from the magnetic resonance images. A comparison of serial measurements was made by examining the changes in LV mass by all 3 techniques in those completing an exercise program (n=140). The cube-function technique showed a consistent underestimation of LV mass of 14.3 g, and there were wide 95% limits of agreement (±57.6 g and ±46.3 g for cube-function and area-length techniques, respectively) when compared with 3D measurement. There were similarly wide limits of agreement for the change in mass (±55.2 g and ±44.8 g for cube-function and area-length, respectively). The assumption of geometric shape in the cube-function and area-length formulas resulted in significant variation in LV mass estimates from direct measurement by using a 3D technique. The technique cannot be recommended either at a single time point or for serial studies in small populations; 3D imaging techniques, such as cardiovascular magnetic resonance, are preferable.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—The association of insulin resistance and hyperinsulinemia to blood pressure has remained controversial. We examined the association of insulinemia to hypertension and blood pressure using baseline measurements for participants of the Diabetes Prevention Program (DPP). The DPP is a multicenter randomized controlled trial of 3819 participants with impaired glucose tolerance, and is designed to evaluate interventions for the delay or prevention of type 2 diabetes. The relationship between hypertension and insulinemia is described overall and by ethnicity. The effects of demographics (age and gender), adiposity, and glucose on the relationship are also presented. Asian Americans and African Americans had a similarly high prevalence of hypertension as did whites; American Indians had a lower prevalence of hypertension. Among participants not on antihypertensive medications, systolic blood pressure was significantly (but weakly) correlated with fasting insulin (r=0.12), homeostasis model assessment of insulin resistance (HOMA IR;r=0.13), and fasting proinsulin (r=0.10) when adjusted for age and gender (all,P<0.001). Systolic blood pressure showed similar correlations to fasting insulin in each ethnic group. After further adjustment for body mass index, the association of fasting insulin to systolic and diastolic blood pressures weakened considerably but remained significant (systolic:r=0.06,P=0.002; DBP:r=0.06,P<0.001). We conclude that a weak but significant association between insulin, (and proinsulin and HOMA IR) and blood pressure exists but is largely explained by overall adiposity. This association is similar among ethnicities, with the possible exception of Hispanics. The relation between insulin concentrations and blood pressure explains relatively little of the ethnic differences in hypertensive prevalence.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Peroxisome proliferator-activated receptor-&ggr; (PPAR&ggr;) ligands are widely used in patients with insulin resistance and diabetes. Because coronary artery disease is a major complication for such patients, it is important to determine the effects of PPAR&ggr; activation on arteriosclerosis. Long-term inhibition of endothelial NO synthesis by administration ofN&ohgr;-nitro-l-arginine methyl ester (L-NAME) to rats induces coronary vascular inflammation (monocyte infiltration, monocyte chemoattractant protein-1 [MCP-1] expression) and subsequent arteriosclerosis. We examined the effects of pioglitazone (a PPAR&ggr; ligand) in this rat model to determine whether PPAR&ggr; activation with pioglitazone inhibits arteriosclerosis by its indirect effects on metabolic conditions or by direct effects on the cells participating to the pathogenesis of arteriosclerosis. We found that pioglitazone did not affect metabolic states, systolic blood pressure, or serum NO levels, but did prevent the L-NAME–induced coronary inflammation and arteriosclerosis. Pioglitazone did not reduce local expression of MCP-1 but markedly attenuated increased expression of the MCP-1 receptor C-C chemokine receptor 2 (CCR2) in lesional and circulating monocytes. PPAR&ggr; activation with pioglitazone prevented coronary arteriosclerosis, possibly by its antiinflammatory effects (downregulation of CCR2 in circulating monocytes). Inhibition of the CCR2-mediated inflammation may represent novel antiinflammatory actions of pioglitazone beyond improvement of metabolic state.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Ghrelin is an orexigenic peptide originally isolated from the stomach. Intravenous administration of ghrelin has been shown to elicit a decrease in arterial pressure without a significant change in heart rate (HR), suggesting that ghrelin may act on the central nervous system to modulate sympathetic activity. The aim of the present study was to determine the central effects of ghrelin on cardiovascular and sympathetic responses in conscious rabbits. Intravenous injection of ghrelin elicited dose-related decreases in arterial pressure and HR, without a significant change in renal sympathetic nerve activity. On the other hand, intracerebroventricular injection of 1 nmol of ghrelin decreased arterial pressure, HR, and renal sympathetic nerve activity. Peak depressor or sympathoinhibitory responses of mean arterial pressure and renal sympathetic nerve activity (−19.0±1.5 mm Hg and −43.3±5.4%) were observed at 50 and 40 minutes, respectively, after intracerebroventricular injection of 1 nmol of ghrelin. Furthermore, a subdepressor dose of intracerebroventricular infusion of ghrelin (0.3 nmol/150 &mgr;L per hour) significantly augmented the baroreflex sensitivities assessed by renal sympathetic nerve activity and HR compared with those of vehicle infusion (Gmax; −17.8±3.1 versus −9.4±1.6%/mm Hg,P<0.05; −12.5±1.8 versus −6.6±1.2 bpm/mm Hg,P<0.05; respectively). These results suggest that intravenous injection of ghrelin acts, at least in part, on the central nervous system to decrease arterial pressure and renal sympathetic nerve activity, and that central ghrelin participates in the regulations of the sympathetic nerve activity to the kidney and the baroreceptor reflex in conscious rabbits.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—We previously reported that inhibition of epidermal growth factor receptor tyrosine kinase activity attenuates renal arteriolar contractile responses to angiotensin II. We performed the present experiments to determine if epidermal growth factor receptor tyrosine kinase activity contributes to the afferent arteriolar intracellular [Ca2+] response to angiotensin II. Afferent arterioles were dissected from rat kidney and intracellular [Ca2+] was monitored with the use of fura-2. In normal Ringer’s bath containing 1.5 mmol/L Ca2+, basal intracellular [Ca2+] averaged 95±7 nmol/L and 100 nmol/L angiotensin II caused a rapid rise (peak &Dgr;=75±10 nmol/L) that waned to a plateau averaging 24±5 nmol/L above baseline. Pretreatment with 100 nmol/L AG1478 (epidermal growth factor receptor tyrosine kinase inhibitor) reduced both the peak and the plateau stages of the angiotensin II response (peak &Dgr;=42±7 nmol/L; plateau &Dgr;=8±4 nmol/L). A structurally unrelated epidermal growth factor receptor tyrosine kinase inhibitor also suppressed the peak response to angiotensin II, whereas tyrosine phosphatase inhibition enhanced the plateau phase of the response. In the presence of 100 nmol/L extracellular Ca2+, the angiotensin II response was characterized by a peak of diminished magnitude (&Dgr;=49±10 nmol/L;P<0.05 versus the response in normal Ringer’s bath) with no plateau, and this response was unaffected by AG1478. Moreover, angiotensin II stimulation of divalent cation influx (Mn2+quench of fura-2 fluorescence) was decreased significantly by AG1478. We conclude that epidermal growth factor receptor tyrosine kinase activity contributes to the afferent arteriolar intracellular [Ca2+] response to angiotensin II and that this process involves promotion of Ca2+influx.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—Although angiotensin (Ang) II is known to regulate renal proximal transport in a biphasic way, the receptor subtype(s) mediating these Ang II effects remained to be established. To clarify this issue, we compared the effects of Ang II in wild-type mice (WT) and Ang II type 1A receptor–deficient mice (AT1AKO). The Na+-HCO3−cotransporter (NBC) activity, analyzed in isolated nonperfused tubules with a fluorescent probe, was stimulated by 10−10mol/L Ang II but was inhibited by 10−6mol/L Ang II in WT. Although valsartan (AT1antagonist) blocked both stimulation and inhibition by Ang II, PD 123,319 (AT2antagonist) did not modify these effects of Ang II. In AT1AKO, in contrast, this biphasic regulation was lost, and only stimulation of NBC activity by 10−6mol/L Ang II was observed. This stimulation was blocked by valsartan but not by PD 123,319. More than 10−8mol/L Ang II induced a transient increase in cell Ca2+concentrations in WT, which was again blocked by valsartan but not by PD 123,319. However, up to 10−5mol/L Ang II did not increase cell Ca2+concentrations in AT1AKO. Finally, the addition of arachidonic acid inhibited the NBC activity similarly in WT and AT1AKO, suggesting that the inhibitory pathway involving P-450 metabolites is preserved in AT1AKO. These results indicate that AT1Amediates the biphasic regulation of NBC. Although low-level expression of AT1Bcould be responsible for the stimulation by 10−6mol/L Ang II in AT1AKO, no evidence was obtained for AT2involvement.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID

摘要:

Abstract—The goal of the present study was to evaluate the role of endoglin, a transforming growth factor-&bgr;1 (TGF-&bgr;1) accessory receptor, in the pathogenesis of renal fibrosis. This was achieved by testing a model of tubulo-interstitial fibrosis induced by unilateral ureteral obstruction in endoglin heterozygous (Eng+/−) mice. Northern and Western blot analysis revealed that endoglin expression in kidneys of these mice was significantly reduced compared withEng+/+littermates. Pronounced interstitial fibrosis induced by ureteral obstruction was confirmed histologically by Masson’s trichromic staining and by increased immunostaining for fibronectin and laminin without significant differences betweenEng+/−andEng+/+mice. Ureteral obstruction induced significant increases in &agr;2(I) and &agr;1(IV) collagen, fibronectin, and TGF-&bgr;1 mRNA levels, as well as in total kidney collagen but changes were similar inEng+/−andEng+/+mouse kidneys. Ureteral obstruction also induced a 2-fold increase in endoglin mRNA levels in bothEng+/+mice andEng+/−mice, which was confirmed by Western blot analysis. Thus, the present study provides clear evidence that endoglin is upregulated in the kidneys of mice with interstitial fibrosis induced by unilateral ureteral ligation. However,Eng+/−mice do not show any changes in the severity of renal disease induced in this model when compared with normal mice, suggesting that the absolute level of endoglin is not critical for the effects of TGF-&bgr;1 in the renal fibrosis process.

ISSN:0194-911X    

出版商:OVID    

年代:2002

数据来源: OVID