A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted

Nagendran, Jayan; Gurtu, Vikram; Fu, David; Dyck, Jason R.B.; Haromy, Alois; Ross, David B.; Rebeyka, Ivan M.; Michelakis, Evangelos D.

doi:10.1016/j.jtcvs.2008.01.040

Cited by 89 publications

(80 citation statements)

References 40 publications

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“…In contrast in RV-PAB there was downregulation of transcripts for actin and cytoskeleton protein binding, intracellular transport, and the sarcomere and myofibril. This would agree with previous reports that have suggested that in RV hypertrophy, mitochondrial and metabolic remodeling are the predominant changes in growing animals as well as in adult hypertrophy models (1,6,27,32). The downregulation of these mechanoskeletal processes occurring in the RV but not in the LV would account for the more rapid progression to contractile failure in RV-PAB compared with LV-AOB.…”

Section: H704supporting

confidence: 92%

Pressure-overload hypertrophy of the developing heart reveals activation of divergent gene and protein pathways in the left and right ventricular myocardium

Friehs

Cowan

Choi

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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and left ventricular (LV) myocardium differ in their pathophysiological response to pressure-overload hypertrophy. In this report we use microarray and proteomic analyses to identify pathways modulated by LV-aortic banding (AOB) and RV-pulmonary artery banding (PAB) in the immature heart. Newborn New Zealand White rabbits underwent banding of the descending thoracic aorta [LV-AOB; n ϭ 6]. RV-PAB was achieved by banding the pulmonary artery (n ϭ 6). Controls (n ϭ 6 each) were sham-manipulated. After 4 (LV-AOB) and 6 (RV-PAB) wk recovery, the hearts were removed and matched RNA and proteins samples were isolated for microarray and proteomic analysis. Microarray and proteomic data demonstrate that in LV-AOB there is increased transcript expression levels for oxidative phosphorylation, mitochondria energy pathways, actin, ILK, hypoxia, calcium, and protein kinase-A signaling and increased protein expression levels of proteins for cellular macromolecular complex assembly and oxidative phosphorylation. In RV-PAB there is also an increased transcript expression levels for cardiac oxidative phosphorylation but increased protein expression levels for structural constituents of muscle, cardiac muscle tissue development, and calcium handling. These results identify divergent transcript and protein expression profiles in LV-AOB and RV-PAB and provide new insight into the biological basis of ventricular specific hypertrophy. The identification of these pathways should allow for the development of specific therapeutic interventions for targeted treatment and amelioration of LV-AOB and RV-PAB to ameliorate morbidity and mortality.heart; hypertrophy; microarray; proteomics VENTRICULAR OUTFLOW TRACT obstruction in congenital heart defects such as interrupted aortic arch, coarctation of the aorta on the left side, and pulmonary artery stenosis on the right side, causes progressive cardiac hypertrophy and, if unrelieved, leads to ventricular dilatation with contractile dysfunction and ultimately irreversible heart failure. Initially, the myocardium compensates to elevated pressure-loading by increasing wall thickness to normalize wall stress. These changes allow for maintenance of contractile function in left ventricular pressureoverload hypertrophy [LV-aortic banding (AOB)], whereas in right ventricular pressure-overload hypertrophy [RV-pulmonary artery banding (PAB)] these changes are less effective and progression to failure occurs more rapidly (2, 4, 15).Our previous studies using the rabbit model of LV-AOB and RV-PAB have demonstrated that disease progression involves both cellular and extracellular components of the myocardium. We have demonstrated that changes in cardiomyocyte viability, lack of adaptive capillary growth, fibrosis, and response to metabolic stress are differentially regulated in LV-AOB and RV-PAB (11,13,16,20). However, the mechanisms involved in the compensated phase of LV-AOB and RV-PAB have yet to be clearly elucidated. In this report we present microarray and proteomic analyses of the LV and RV during t...

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Section: H704supporting

confidence: 92%

Pressure-overload hypertrophy of the developing heart reveals activation of divergent gene and protein pathways in the left and right ventricular myocardium

Friehs

Cowan

Choi

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…23 Some of these differences are detailed in the following text and are summarized in Table 2. [24][25][26][27][28][29][30][31][32][33][34] Likewise, there are differences in the RV response to certain effectors, including adrenergic hormones. Although α1-adrenergic agonists increase LV contractility, they may decrease RV contractility.…”

Section: Rv Versus LV Failure 1035mentioning

confidence: 99%

“…These metabolic changes may subsequently lead to hyperpolarization of the mitochondrial membrane potential in RV hypertrophy, inefficient energy metabolism, and increased lactate production at an earlier stage of maladaptation compared with the LV. 26 These molecular effects have potential therapeutic implications specific for the pressure-loaded RV. For example, dichloroacetate, Figure 2.…”

Section: Rv Versus LV Failure 1035mentioning

confidence: 99%

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Right Versus Left Ventricular Failure

2014

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1033V entricular failure manifests in many forms, its underlying physiology ranging from overt left ventricular (LV) systolic dysfunction to isolated right ventricular (RV) diastolic dysfunction, and the wide portfolio of resulting symptoms vary from chronic fluid retention to acute multiorgan dysfunction and death. In this review, we discuss the morphological, functional, and molecular similarities and differences in RV and LV responses to adverse loading and failure. We further discuss whether LV and RV function and failure can truly be discussed as separate entities and thereby examine interactions between the ventricles that on one hand contribute to ventricular dysfunction but on the other may be harnessed for therapeutic benefit. Embryological and Physiological Differences Between the RV and LVThe RV and LV have different embryological origins.1 The LV originates from the primary heart field; the RV, from the secondary heart field. Consequently, several genes specifically control RV formation, including, among others, Hand2 and Tbx20.2 During gestation, the RV functions as the systemic ventricle ( Figure 1A). During fetal life, in addition to supplying the modest amount of pulmonary blood flow, the RV pumps blood to the lower body and placenta and contributes more than half of the combined cardiac output.3 With the transition from fetal to postnatal physiology and with the reduction in pulmonary vascular resistance, the subpulmonary RV transforms its morphology and geometry, becoming a thin-walled chamber to adopt its postnatal physiological characteristics. 4 Because it faces a low impedance pulmonary circulation, the normal postnatal RV maintains a cardiac output equal to that of the LV at approximately a fifth of the energy cost. The trapezoidal RV pressure-volume loop reflects this difference, with few if any isovolumic periods. Consequently, RV output starts early during pressure generation and is later maintained by a "hangout period" when antegrade flow continues into the pulmonary artery despite the onset of RV relaxation.5 In contrast, the rectangular LV pressure-volume loops reflect the LV square-wave pump function with distinct and well-developed isovolumic contraction and relaxation periods.6 Likewise, RV myocytes display faster twitch velocities than LV myocytes. 7The physiological differences are reflected in morphological differences between the ventricles (Table 1). The low-pressure RV is triangular in the sagittal plane and crescent-shaped in cross section as a result of the concave RV free wall and convex interventricular septum wrapping around the high-pressured, thick-walled, bullet-shaped LV. Consequently, although the normal RV has a lower ratio of volume to surface area and a thinner wall than the LV, 8 the low cavity pressure determines a lower wall stress and lower oxygen demands.Anatomic differences are also apparent in myocardial architecture. LV subepicardial and subendocardial fibers are oblique and helical with fiber angles ranging from 30° to 80° with a mean of ≈60°, whereas ...

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“…Current work in the field has advanced our understanding of RV myocyte pathobiology significantly in the context of pulmonary vascular disease, particularly with respect to maladaptive molecular mechanisms that modulate RV failure through changes in cellular metabolism, 10 nitric oxide bioavailability, 11,12 and ion channel dysfunction. 13 These basic and translational scientific models, which emphasize novel RV-specific targets to improve RV performance, have illuminated a number of cell-signaling pathways with future therapeutic promise for patients afflicted with pulmonary hypertension-induced RV dysfunction.…”

Section: Article See P 2859mentioning

confidence: 99%

Targeting Neurohumoral Signaling to Treat Pulmonary Hypertension

Maron

2012

Circulation

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A dverse remodeling of the right ventricle (RV) that affects RV systolic or diastolic function directly or indirectly by modulating changes to cavitary geometry is a principal determinant of poor outcome across the global spectrum of cardiopulmonary diseases. 1,2 Indeed, even subclinical increases in RV mass are associated with substantially elevated risk for future heart failure and decreased lifespan. 3 Unique embryological and anatomic features of the RV provide a pathophysiological basis by which to account for this observation. For example, precursor cells of the RV and left ventricle (LV) derive from the primary and anterior heart fields, 4 respectively, indicating a different cellular lineage for each ventricle despite their close proximity and placement in series. In contrast to the LV, the RV is a triangular structure that is thin walled and noncompacted, and, thus, tolerates pressure-loading conditions poorly. 5 Moreover, poor coronary blood flow reserve with increased RV strain due to elevations in wall tension is associated with decreased RV microvascular perfusion. 6 Article see p 2859Although these properties establish the RV-specific pressure-volume relationship profile, factors that precipitate impaired RV performance are less well characterized. Take, for example, the wide swath of classical reports that describe LV hemodynamic (patho)physiological responses to acute and chronic myocardial ischemia, systemic hypertension, valvular dysfunction, and pericardial disease. 7 By contrast, a paucity of data exists to characterize the mechanistic and clinical contributions of similar processes (including LV dysfunction) to the natural history of adverse RV remodeling in noncongenital heart disease patients, despite the attendant clinical relevance of RV failure. Furthermore, the basic mechanism(s) that underpin RV dysfunction when contemporaneous with pulmonary hypertension, the most common end-pathophenotype associated with changes to RV loading, 8 are largely unknown. In fact, only recently has consideration been given to RV function within the context of the larger lung-pulmonary circulatory-RV apparatus. 5,9 This is a critical distinction, however, because defining the right heart axis in this way reidentifies the RV as a specific participant in the pathobiology of pulmonary hypertension and potential therapeutic target per se, thereby parting from traditional dogma in which RV dysfunction is a consequence of pulmonary vascular disease, an indicator of irreversible cardiac injury, and a dismal prognostic marker.Current work in the field has advanced our understanding of RV myocyte pathobiology significantly in the context of pulmonary vascular disease, particularly with respect to maladaptive molecular mechanisms that modulate RV failure through changes in cellular metabolism, 10 nitric oxide bioavailability, 11,12 and ion channel dysfunction. 13 These basic and translational scientific models, which emphasize novel RV-specific targets to improve RV performance, have illuminated a number of cell-sig...

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A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted

Cited by 89 publications

References 40 publications

Pressure-overload hypertrophy of the developing heart reveals activation of divergent gene and protein pathways in the left and right ventricular myocardium

Pressure-overload hypertrophy of the developing heart reveals activation of divergent gene and protein pathways in the left and right ventricular myocardium

Right Versus Left Ventricular Failure

Targeting Neurohumoral Signaling to Treat Pulmonary Hypertension

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