Pressure overload and neurohumoral activation differentially affect the myocardial proteome

Abstract

Treatment with monocrotaline causes pulmonary hypertension in rats. This results in severe pressure overload-induced hypertrophy of the right ventricles, whilst the normally loaded left ventricles do not hypertrophy. Both ventricles are affected by enhanced neuroendocrine stimulation in this model. We analyzed in this model load-induced and catecholamine-induced changes of right and left ventricular proteome by two-dimensional gel electrophoresis, tryptic in-gel digest, and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. All analyzed animals showed right ventricular hypertrophy without signs of heart failure. Changes of 27 proteins in the right and 21 proteins in the left ventricular myocardium were found. Given the hemodynamic features of this animal model, proteome changes restricted to the right ventricle are caused by pressure overload. We describe for the first time a potentially novel pathway (BRAP2/BRCA1) that is involved in myocardial hypertrophy. Furthermore, we demonstrate that increased afterload-induced hypertrophy leads to striking changes in the energy metabolism with down-regulation of pyruvate dehydrogenase (subunit beta E1), isocitrate dehydrogenase, succinyl coenzyme A ligase, NADH dehydrogenase, ubiquinol-cytochrome C reductase, and propionyl coenzyme A carboxylase. These changes go in parallel with alterations of the thin filament proteome (troponin T, tropomyosin), probably associated with Ca(2+) sensitization of the myofilaments. In contrast, neurohumoral stimulation of the left ventricle increases the abundance of proteins relevant for energy metabolism. This study represents the first in-depth analysis of global proteome alterations in a controlled animal model of pressure overload-induced myocardial hypertrophy.

Time course and mechanisms of left ventricular systolic and diastolic dysfunction in monocrotaline-induced pulmonary hypertension

“…The slower b-isoform was increased in the LV of both MCT-4 and MCT-6, as previously reported in different models of RV hypertrophy [17,43,46,47]. Changes in the expression of enzymes involved in bioenergetics and cell metabolism such as pyruvate dehydrogenase kinase-4, acetyl-CoA dehydrogenase and mitochondrial ATP synthase [42,43] as well as a reduced capillary proliferation [21] have also been described in the LV of PH rats. Contrastingly, calcium kinetics side, diastolic pressures are nicely matched at all afterload levels in the control animal, but become progressively higher as afterload increases, both in MCT-4 and MCT-6 animals.…”

“…ACE mRNA levels progressively increased in MCT-4 and MCT-6, whereas ET-1 mRNA levels were only increased 6 weeks after MCT injection P \ 0.05: * vs. Ctrl-4; vs. Ctrl-6; à vs. regulator proteins such as the Ca 2? -ATPase of the sarcoendoplasmic reticulum and phospholamban were consistently reported to be unaltered in the non-overloaded LV [21,42,43]. To further explore the underlying mechanisms of LV myocardial dysfunction, we investigated neurohumoral activation, extracellular matrix composition and apoptosis.…”

“…Tenascin-C is synthesized by fibroblasts, highly expressed in embryonic tissues, and upregulated by both mechanical stress [2] and neuroendocrine mediators [34] in adult tissues under pathological conditions such as myocardial infarction [16]. Additionally, several pro-inflammatory cytokines, growth factors and neurohumoral peptides that stimulate tenascin-C synthesis [8,34,42] also participate in myocardial dysfunction induced by MCT [6,33]. Tenascin-C is an important regulator of extracellular matrix and induces several metalloproteinases which activation is implicated in cardiac remodeling [44].…”

Upregulated Neurohumoral Factors are Associated With Left Ventricular Remodeling and Poor Prognosis in Rats With Monocrotaline-Induced Pulmonary Arterial Hypertension

“…20 Seyfarth et al have reported downregulation of the 1,2 receptor-Gs protein-adenylyl cyclase system in both ventricles, although the change in the RV was more prominent than in the LV. 19 As shown in Fig 2, and by Kögler et al, 21 the plasma NA level was significantly increased in MCT-treated rats, suggesting that the downregulation of the adrenergic -receptor may be in part due to catecholamine overload.…”

Resveratrol Ameliorates Cardiac Hypertrophy by Down‐regulation of miR‐155 Through Activation of Breast Cancer Type 1 Susceptibility Protein

“…However, the role of BRCA1 in protecting cardiac tissue from DNA damage has not been fully explored to date. In a recent study, Gerd Hasenfuss et al 11. described, for the first time, a potentially novel signaling pathway (BRAP2/BRCA1) that was involved in the process of myocardial hypertrophy.…”