Apoptosis en las enfermedades cardiovasculares

Apoptosis consists of a distinct form of cell death that displays characteristic alterations in cell morphology and cell fate which are different than death due to oncosis or necrosis. In terms of tissue kinetics, apoptosis may be considered a mechanism that counterbalances the effect of cell proliferation by mitotic division. In fact, deregulated apoptosis has been implicated in the development a wide variety of human diseases. Excessive apoptotic cell death may cause organ atrophy and organ failure. On the other hand, insufficient elimination of redundant cells may lead to organ and tissue structural remodeling. In recent years, apoptosis has become a highly fashionable and competitive area of research. Fortunately, it has not escaped the attention of the cardiovascular community. Sightings of apoptosis have been reported from every corner of cardiovascular medicine ranging from conduction system defects to congestive heart failure, and from atherosclerosis to aneurysms. There is no question that these sightings will eventually be converted into mechanistic etiopathogenic and physiopathological insights and will form the basis for designing new diagnostic modalities and novel therapies

Review of the molecular pharmacology of Losartan and its possible relevance to stroke prevention in patients with hypertension

BACKGROUND: The Losartan Intervention For End-point reduction in hypertension (LIFE) study found that a losartan-based regimen, compared with an atenolol-based regimen, resulted in a significantly lower risk of stroke in hypertensive patients with left ventricular hypertrophy, despite similar reductions in blood pressure. OBJECTIVE: The purpose of this review was to examine the molecular and pharmacologic mechanisms that may be associated with the different outcomes observed in the LIFE study. METHODS: A PubMed/MEDLINE search of English-language articles (1990 to February 2006) with the terms angiotensin II antagonists or AIIAs or angiotensin receptor blockers or losartan or atenolol or beta blocker and terms including, but not limited to, atherosclerosis, left ventricular hypertrophy, carotid artery hypertrophy, fatty streaks, atrial fibrillation, arrhythmias, endothelial function, myocyte hypertrophy, myocardial fibrosis, platelet aggregation, tissue factor, plasminogen activator inhibitor-1, PAI-1, anti-inflammatory, uric acid, or oxidative stress. RESULTS: Losartan's significant effect on stroke may be related to several possible mechanisms that are independent of blood-pressure reductions. These include improvements in endothelial function and vascular structure; decreases in vascular oxidative stress; reductions in left ventricular hypertrophy, reductions in myocardial fibrosis, or both; and modulation of atherosclerotic disease progression. Although some of these effects may be shared by other angiotensin II receptor antagonists (AIIAs), and perhaps other anti-hypertensive classes (eg, angiotensin-converting enzyme inhibitors), the ability of losartan to lower serum uric acid levels-a proposed independent risk factor for cardiovascular disease-appears to be a molecule-specific effect. Alternative explanations of the results of the LIFE study have also been hypothesized, including inappropriate choice of atenolol as an active comparator and differences in central pulse pressures between study groups. CONCLUSIONS: This review of the literature suggests that losartan (and perhaps other AIIAs) may possess a number of properties, independent of its antihypertensive effects, that may be associated with decreased vulnerability of the plaque, myocardium, and blood

Differential hypertrophic effects of cardiotrophin-1 on adult cardiomyocytes from normotensive and spontaneously hypertensive rats

Cardiotrophin-1 (CT-1) produces longitudinal elongation of neonatal cardiomyocytes, but its effects in adult cardiomyocytes are not known. Recent observations indicate that CT-1 may be involved in pressure overload left ventricular hypertrophy (LVH). We investigated whether the hypertrophic effects of CT-1 are different in cardiomyocytes isolated from adult normotensive and spontaneously hypertensive rats (SHR). Hypertrophy was evaluated by planimetry and confocal microscopy, contractile proteins were quantified by Western blotting and real-time RT-PCR, and intracellular pathways were analyzed with specific chemical inhibitors. CT-1 increased c-fos and ANP expression (p<0.01) and cell area (p<0.01) in cardiomyocytes from both rat strains. In Wistar cells, CT-1 augmented cell length (p<0.01) but did not modify either the transverse diameter or cell depth. In SHR cells, CT-1 increased cell length (p<0.05), cell width (p<0.01) and cell depth, augmented the expression of myosin light chain-2v (MLC-2v) and skeletal alpha-actin (p<0.01) and enhanced MLC-2v phosphorylation (p<0.01). The blockade of gp130 or LIFR abolished CT-1-induced growth in the two cell types. All distinct effects observed in cardiomyocytes from SHR were mediated by STAT3. Baseline angiotensinogen expression was higher in SHR cells, and CT-1 induced a 1.7-fold and 3.2-fold increase of angiotensinogen mRNA in cardiomyocytes from Wistar rats and SHR respectively. In addition, AT1 blockade inhibited the specific effects of CT-1 in SHR cells. Finally, ex vivo determinations revealed that adult SHR exhibited enhanced myocardial CT-1 (mRNA and protein, p<0.01), increased cell width (p<0.01) and concentric LVH compared with pre-hypertensive SHR. These findings reveal a specific cell-broadening effect of CT-1 in cardiomyocytes from adult SHR and suggest that the hypertensive phenotype of these cells may influence the hypertrophic effects of CT-1, probably by means of an exaggerated induction of angiotensinogen expression. We suggest that CT-1 might facilitate LVH in genetic hypertension through a cross-talk with the renin-angiotensin system

Fibrosis in hypertensive heart disease: role of the renin-angiotensin-aldosterone system

Structural homogeneity of cardiac tissue is governed by mechanical and humoral factors that regulate cell growth, apoptosis, phenotype, and extracellular matrix turnover. ANGII has endocrine, autocrine, and paracrine properties that influence the behavior of cardiac cells and matrix by AT1 receptor binding. Various paradigms have been suggested, including ANGII-mediated up-regulation of collagen types I and III formation and deposition in cardiac conditions, such as HHD. A growing body of evidence, however, deals with the potential role of aldosterone, either local or systemic, in inducing cardiac fibrosis. Aldosterone might also mediate the profibrotic actions of ANGII. To reduce the risk of heart failure that accompanies HHD, its adverse structural remodeling (eg, myocardial hypertrophy and fibrosis) must be targeted for pharmacologic intervention. Cardioprotective agents must reverse not only the exaggerated growth of cardiac cells, but also regress existing abnormalities in fibrillar collagen. Available experimental and clinical data suggest that agents interfering with ACE, the AT1 receptor, or the mineralocorticoid receptor may provide such a cardioprotective effect