MircoRNAs (miRNAs) are small non-coding RNAs that govern the gene expression and, play significant role in the pathogenesis of heart failure. The detection of miRNAs in circulation of pulmonary hypertensive (PH) human subjects remains elusive. In the current study, we determined the pattern of miRNAs of mild-to-severe human PH subjects and, compared them with the control subjects by miRNA array. Blood was obtained using fluoroscopic and waveform guided catheterization from the distal (pulmonary artery) port of the catheter. A total 40 human subjects were included in the study and, the degree of PH was determined by mean pulmonary arterial pressure. Among several miRNAs in the array, we validated 14 miRNAs and, the data were consistent with the array profile. We identified several novel downregulated miRNAs (miR-451, miR-1246) and upregulated miRNAs (miR-23b, miR-130a and miR-191) in the circulation of PH subjects. Our study showed novel set of miRNAs which are dysregulated in PH and, are directly proportional to the degree of PH. These miRNAs may be considered as potential biomarker for early detection of PH.

P ulmonary arterial hypertension (PAH) is characterized by multicellular vascular lesions which obstruct and obliterate pulmonary arteries. The occluded vessels impede blood flow and increase right ventricular (RV) afterload leading to RV hypertrophy (RVH) and RV failure.1,2 The pathogenesis of PAH is multifactorial and involves vascular cell remodeling including pulmonary arterial endothelial cell (EC) dysfunction and pulmonary arterial smooth muscle cell proliferation. 3,4 Treatment regimens for PAH include inhaled nitric oxide, vasodilators, calcium channel blockers, intravenous prostacyclin, and endothelin receptor antagonists, which fail to fully reverse this disease.5 Identifying key pathways is, therefore, required for the development of new targeted therapeutics.Nuclear factor-κB (NF-κB) is a key transcriptional regulator in various cardiac disorders (myocardial infarction, hypertrophy, and dilated cardiomyopathy, etc), 6,7 but the role of NF-κB remains limited in PAH-induced vascular remodeling and RVH. Recent few reports advocate the critical role of NF-κB in the progression or setting of PAH, [8][9][10] but the underlying mechanism of monocrotaline (MCT)-induced PAH and its progression to the development of RVH remains elusive. MCT is a plant alkaloid contained in the seeds of Crotalaria spectalalia and its metabolite, MCT pyrrole, injures the ECs of pulmonary blood vessels.11 It is suggested that MCT treatment causes direct damage of ECs, increases alveolar capillary permeability, and induces inflammation that triggers the development of PAH and further progresses to RVH.12-14 Despite its frequent use for many decades, the basic mechanism underlying PAH induction by MCT has not been fully understood.We demonstrated previously that MCT-treated PAH-induced RVH was attenuated in cardiac-specific IκBα triple mutant transgenic mice, compared with wild-type (WT) mice, suggesting a protective role of NF-κB in RVH. 15 We identified bone morphogenetic protein (BMP), BMP receptor (BMPR), inhibitor of differentiation (Id), SMAD, and the Notch (BMP-SMAD-Id-Notch) axis as an integral signaling Abstract-Pulmonary arterial hypertension (PAH) is a devastating cardiopulmonary disorder with significant morbidity and mortality in patients with various lung and heart diseases. PAH is characterized by vascular obstruction which leads to a sustained increased pulmonary vascular resistance, vascular remodeling, and right ventricular hypertrophy and failure. Limited PAH therapies indicate that novel approaches are urgently needed for the treatment of PAH. Nuclear factor-κB (NF-κB) has been shown to play an important role in different cardiac pathologies; however, the role of NF-κB remains limited in the setting of PAH. Here, we investigated whether NF-κB inhibition in the lungs using Club (Clara) cell-10 promoter driving IκBα mutant had any effect in monocrotaline (MCT)-induced PAH mouse model. Our data revealed that MCT-induced PAH and right ventricular hypertrophy were associated with NF-κB activation, inflammatory respon...

ObjectivesThe purpose of this study was to evaluate the antiarrhythmic potential of mesenchymal stem cells (MSC) under a different environment.

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).