Tumor necrosis factor alpha and glutathione interplay in chronic heart failure.

The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.

Effect of pressure overload on angiotensin receptor expression in the rat heart during early postnatal life.

The development of cardiac hypertrophy during neonatal life and in adults implies different processes. The angiotensin II (Ang II) system is involved in the development of cardiac hypertrophy in adults, but its role in neonates remains unclear. The aim of this study was to estimate the influence of increased hemodynamic load on the developmental pattern of the AT1/AT2 receptor expression in the heart. Two-day-old rats submitted to abdominal aortic constriction (AC) or sham operation were sacrificed 2 h, and 1, 3, and 8 days after surgery. Ang II was evaluated in sera and immunohistology was performed to define the cardiac hypertrophy process. The Ang II receptor subtypes 1 and 2 were quantified at the receptor and mRNA levels by(125)I-Ang II binding and RT-PCR, respectively. Ang II content in sera increased transiently 2 h after surgery in the AC group. In sham-operated, AT1 and AT2 decreased throughout the period studied at both mRNA and receptor levels. However, the AT1 mRNA level decrease was more pronounced than that of AT2 (by 57% and 27%, respectively). AC not only prevented the postnatal decrease in AT mRNA level but resulted in an increase in AT1 mRNA 8 days after surgery (P<0.05). Besides in the AC groups, AT2 mRNA levels but not those of AT1 mRNA were linearly correlated with the left ventricular mass. At the receptor level, a significant transient (1 day after surgery) increase in both AT1 and AT2 was observed. In conclusion, our data demonstrated that imposition of pressure overload soon after birth altered the pattern of AT receptor expression.

Modulation of angiotensin II receptor expression during development and regression of hypoxic pulmonary hypertension.

Lung vessel muscularization during hypoxic pulmonary hypertension is associated with local renin-angiotensin system activation. The expression of angiotensin II (Ang II) AT1 and AT2 receptors in this setting is not well known and has never been investigated during normoxia recovery. We determined both chronic hypoxia and normoxia recovery patterns of AT1 and AT2 expression and distal muscularization in the same lungs using in situ binding, reverse transcriptase/polymerase chain reaction, and histology. We also used an isolated perfused lung system to evaluate the vasotonic effects of AT1 and AT2 during chronic exposure to hypoxia with and without subsequent normoxia recovery. Hypoxia produced right ventricular hypertrophy of about 100% after 3 wk, which reversed with normoxia recovery. Hypoxia for 2 wk was associated with simultaneous increases (P<0.05) in AT1 and AT2 binding (16-fold and 18-fold, respectively) and in muscularized vessels in alveolar ducts (2. 8-fold) and walls (3.7-fold). An increase in AT2 messenger RNA (mRNA) (P<0.05) was also observed, whereas AT1 mRNA remained unchanged. After 3 wk of hypoxia, muscularization was at its peak, whereas all receptors and transcripts showed decreases (P<0.05 versus hypoxia 2 wk for AT1 mRNA), which became significant after 1 wk of normoxia recovery (P<0.05 versus hypoxia 2 wk). Significant reversal of muscularization (P<0.01) was found only after 3 wk of normoxia recovery in alveolar wall vessels. Finally, the AT1 antagonist losartan completely inhibited the vasopressor effect of Ang II in hypoxic and normoxia-restored lungs, whereas the AT2 agonist CGP42112A had no effect. Our data indicate that in lungs, chronic hypoxia-induced distal muscularization is associated with early and transient increases in AT2 and AT1 receptors probably owing to hypoxia- dependent transcriptional and post-transcriptional regulatory mechanisms, respectively. They also indicate that the vasotonic response to Ang II is mainly due to the AT1 subtype.

Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein E-deficient mice.

BACKGROUND: To define the role of metalloproteinases (MMPs) in the development of lipid-rich atherosclerotic lesions in relation to the balance between proteolytic and antiproteolytic activities, we investigated the impact of adenovirus-mediated elevation in the circulating levels of human tissue inhibitor of MMP (TIMP-1) in atherosclerosis-susceptible apolipoprotein E-deficient (apoE(-/-)) mice. METHODS AND RESULTS: Infusion of apoE(-/-) mice fed a lipid-rich diet with rAd.RSV.TIMP-1 (1x10(11) viral particles) resulted in high hepatic expression of TIMP-1. At 2 weeks after injection, plasma TIMP-1 levels ranged from 7 to 24 micrograms/mL (mean 14.8+/-6.8). Marked overexpression of TIMP-1 was transient, with levels of TIMP-1 decreasing to 2.5 to 8 micrograms/mL (mean 4.3+/-2.1) at 4 weeks. Plasma lipid and lipoprotein levels in mice treated with rAd.RSV.TIMP-1 were similar to those treated with rAd.RSV.betaGal. However, rAd.RSV.TIMP-1-infused mice displayed a marked reduction (approximately 32%; P<0.05) in mean lesion area per section (512+/-121 micrometers(2)x10(3); n=12 sections from 4 animals) as compared with rAd.RSV.betaGal-infused mice (750+/-182 micrometers(2)x10(3); n=12 sections from 4 animals). Similarly, marked reduction in macrophage deposition as well as MMP-2, MMP-3, and MMP-13 antigens was observed. CONCLUSIONS: Histological and immunohistologic analyses of atherosclerotic lesions revealed increases in collagen, elastin, and smooth muscle alpha-actin content in mice treated with rAd.RSV.TIMP-1. These qualitative and quantitative features were the consequence of TIMP-1 infiltration from plasma to arterial intima, as immunohistochemical analyses revealed an abundance of TIMP-1 specifically in lesions of rAd.RSV. TIMP-1-treated mice.