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ABSTRACT: Multiple studies have demonstrated the important role of the nuclear factor kappa B (NF-κB) in cardiac pathology. However, these studies' conclusions differ regarding whether NF-κB is protective or detrimental for heart function. This disagreement is not surprising considering the complexity of NF-κB signaling that involves multiple components and regulation at several steps. Furthermore, NF-κB is a pleiotropic transcription factor that receives signals from multiple pathways, including the renin-angiotensin system (RAS) and cytokines, 2 important modulators of cardiac remodeling.
In this article, we review studies related to the role and mechanisms of NF-κB activation in the heart, particularly with regard to the RAS, inflammation, and diabetes. The objective of this review is to consolidate multiple, often contradictory, findings to develop a clear understanding of NF-κB signaling in the heart.
The studies we review demonstrate that NF-κB effects in the heart are mechanism specific and that NF-κB signaling is cyclical. Consequently, the timing of NF-κB measurement is critical, and studies focused on temporal changes in the NF-κB mechanism would help clarify its multiple roles in cardiac pathophysiology.
Ochsner Journal 01/2013; 13(1):157-65.
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ABSTRACT: Hyperglycemia upregulates intracellular angiotensin II production in cardiac myocytes, effects of which are blocked more effectively by renin inhibition than angiotensin receptor blockers (ARBs) or ACE inhibitors. Here we determined whether renin inhibition is more effective at preventing diabetic cardiomyopathy than an ARB or ACE inhibitor. Diabetes was induced in adult mice for 10 wks by streptozotocin. Diabetic mice were treated with insulin, aliskiren (renin inhibitor), benazeprilat (ACE inhibitor), or valsartan (ARB) via subcutaneous minipumps. Significant impairment in diastolic and systolic cardiac function was observed in diabetic mice, which was completely prevented by all three RAS inhibitors. Hyperglycemia significantly increased cardiac oxidative stress and circulating inflammatory cytokines, which were blocked by aliskiren and benazeprilat, while valsartan was partially effective. Diabetes increased cardiac (pro)renin receptor (PRR) expression and nuclear translocation of promyelocytic zinc finger protein (PLZF), which was completely prevented by aliskiren and valsartan, and partially by benazeprilat. Renin inhibition provided similar protection of cardiac function as ARBs and ACE inhibitors. Activation of PLZF by PRR represented a novel mechanism in diabetic cardiomyopathy. Differential effects of the three agents on oxidative stress, cytokines, and PRR expression suggested subtle differences in their mechanism of action.
Clinical Science 11/2012; · 4.61 Impact Factor
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ABSTRACT: The RAS (renin-angiotensin system) is one of the earliest and most extensively studied hormonal systems. The RAS is an atypical hormonal system in several ways. The major bioactive peptide of the system, AngII (angiotensin II), is neither synthesized in nor targets one specific organ. New research has identified additional peptides with important physiological and pathological roles. More peptides also mean newer enzymatic cascades that generate these peptides and more receptors that mediate their function. In addition, completely different roles of components that constitute the RAS have been uncovered, such as that for prorenin via the prorenin receptor. Complexity of the RAS is enhanced further by the presence of sub-systems in tissues, which act in an autocrine/paracrine manner independent of the endocrine system. The RAS seems relevant at the cellular level, wherein individual cells have a complete system, termed the intracellular RAS. Thus, from cells to tissues to the entire organism, the RAS exhibits continuity while maintaining independent control at different levels. The intracellular RAS is a relatively new concept for the RAS. The present review provides a synopsis of the literature on this system in different tissues.
Clinical Science 09/2012; 123(5):273-84. · 4.61 Impact Factor
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ABSTRACT: Uncontrolled pulmonary arterial hypertension (PAH) results in right ventricular (RV) hypertrophy (RVH), progressive RV failure, and low cardiac output leading to increased morbidity and mortality (McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J. J Am Coll Cardiol 53: 1573-1619, 2009). Although the exact figures of its prevalence are difficult to obtain because of the diversity of identifiable causes, it is estimated that the incidence of pulmonary hypertension is seven to nine cases per million persons in the general population and is most prevalent in the age group of 20-40, occurring more commonly in women than in men (ratio: 1.7 to 1; Rubin LJ. N Engl J Med 336: 111-117, 1997). PAH is characterized by dyspnea, chest pain, and syncope. Unfortunately, there is no cure for this disease and medical regimens are limited (Simon MA. Curr Opin Crit Care 16: 237-243, 2010). PAH leads to adverse remodeling that results in RVH, progressive right heart failure, low cardiac output, and ultimately death if left untreated (Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. J Am Coll Cardiol 43: 13S-24S, 2004; Humbert M, Sitbon O, Simonneau G. N Engl J Med 351: 1425-1436, 2004. LaRaia AV, Waxman AB. South Med J 100: 393-399, 2007). As there are no direct tools to assess the onset and progression of PAH and RVH, the disease is often detected in later stages marked by full-blown RVH, with the outcome predominantly determined by the level of increased afterload (D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, et al. Ann Intern Med 115: 343-349, 1991; Sandoval J, Bauerle O, Palomar A, Gomez A, Martinez-Guerra ML, Beltran M, Guerrero ML. Validation of a prognostic equation Circulation 89: 1733-1744, 1994). Various studies have been performed to assess the genetic, biochemical, and morphological components that contribute to PAH. Despite major advances in the understanding of the pathogenesis of PAH, the molecular mechanism(s) by which PAH promotes RVH and cardiac failure still remains elusive. Of all the mechanisms involved in the pathogenesis, inflammation and oxidative stress remain the core of the etiology of PAH that leads to development of RVH (Dorfmüller P, Perros F, Balabanian K, Humbert M. Eur Respir J 22: 358-363, 2003).
AJP Heart and Circulatory Physiology 01/2012; 302(8):H1655-66. · 3.71 Impact Factor
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ABSTRACT: The renin-angiotensin system (RAS) has mainly been categorized as a circulating and a local tissue RAS. A new component of the local system, known as the intracellular RAS, has recently been described. The intracellular RAS is defined as synthesis and action of ANG II intracellularly. This RAS appears to differ from the circulating and the local RAS, in terms of components and the mechanism of action. These differences may alter treatment strategies that target the RAS in several pathological conditions. Recent work from our laboratory has demonstrated significant upregulation of the cardiac, intracellular RAS in diabetes, which is associated with cardiac dysfunction. Here, we have reviewed evidence supporting an intracellular RAS in different cell types, ANG II's actions in cardiac cells, and its mechanism of action, focusing on the intracellular cardiac RAS in diabetes. We have discussed the significance of an intracellular RAS in cardiac pathophysiology and implications for potential therapies.
AJP Regulatory Integrative and Comparative Physiology 12/2011; 302(5):R510-7. · 3.34 Impact Factor
