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

Abstract

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...

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

“…74 Proteomic and microarray analysis reveal increased expression of genes involved in mitochondrial oxidative phosphorylation in left ventricles from rabbit hearts after 4 weeks of aortic banding. 75 To further investigate the contribution of fatty acid oxidation to the development of cardiac hypertrophy and heart failure, pressure overload-induced models of heart failure were studied in genetically modified mice deficient for CPT1b 74 or acetyl CoA carboxylase 2 (ACC2 −/− ). 50 Although the former demonstrate decreased fatty acid oxidation, the latter have higher cardiac fatty acid oxidation rates.…”

Quantitative Phosphoproteomic Study of Pressure-Overloaded Mouse Heart Reveals Dynamin-Related Protein 1 as a Modulator of Cardiac Hypertrophy

“…Proteomic and transcriptomic approaches have been used to study global changes in protein and mRNA expression in hypertrophic hearts (5)(6)(7). Acute pressure overload of the heart leads to altered myocardial energy metabolism (8 -10) and contractile function (9,11,12).…”

Cardiac Tyrosine Hydroxylase Activation and MB-COMT in Dyskinetic Monkeys 

“…Particularly, myocardial tissue obtained from PD patients showed decreased tyrosine hydroxylase positive (TH+) neurons, thus indicating cardiac sympathetic denervation (Orimo et al 2002). In addition, right ventricular (RV) and left ventricular (LV) myocardium have been reported to differ in their pathophysiological response to several factors (Friehs et al 2013). Differences in the genetic make-up, morphology, and functional environment suggest that the RV response to abnormal stress conditions, such as treatment with 1-metil-4-fenil,6-tetrahidropiridine (MPTP) and the undesired peripheral effects of L-DOPA, may differ from that of the LV.…”