Cardiac-specific genetic inhibition of nuclear factor- B prevents right ventricular hypertrophy induced by monocrotaline

Division of Molecular Cardiology, Department of Medicine, College of Medicine, Texas A&M Health Science Center, Scott & White Hospital, Central Texas Veterans Health Care System, Temple, Texas 76504, USA.
AJP Heart and Circulatory Physiology (Impact Factor: 3.84). 01/2012; 302(8):H1655-66. DOI: 10.1152/ajpheart.00756.2011
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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).

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    • "For example, cardiomyocyte-specific IκB kinase (IKK)/NF-κB activation induces reversible inflammatory cardiomyopathy and heart failure (79). In addition, it has been demonstrated in animal models, such as TAC-induced pressure-overload (80, 81) and monocrotaline (MCT)-induced RV hypertrophy (82), that inhibition of NF-kB signaling prevents heart failure (cardiac hypertrophy and/or cardiac remodeling). "
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    • "Interestingly, miR-23b and miR-130a showed target genes for BMPR1b which is degraded during PH and considered as a predictor for PH [33], [34]. Our recent data support this observation where we showed downregulation of BMPR1b, Id1, Id3 and Smad2 in monocrotaline induced mouse PH model [35], but, the functional correlation between the circulatory miRNA and tissue level expression has not been determined. Likewise, the potential role of miR-21 has been defined in few recent studies in PH and vascular remodeling [36], [37], [38]. "
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