Overexpression of Myofibrillogenesis Regulator-1 Aggravates Cardiac Hypertrophy Induced by Angiotensin II in Mice

Abstract

Abstract-Myofibrillogenesis regulator-1 (MR-1) augments cardiomyocytes hypertrophy induced by angiotensin II (Ang II) in vitro. However, its roles in cardiac hypertrophy in vivo remain unknown. Here, we investigate whether MR-1 can promote cardiac hypertrophy induced by Ang II in vivo and elucidate the molecular mechanisms of MR-1 on cardiac hypertrophy. We used a model of Ang II-induced cardiac hypertrophy by infusion of Ang II in female mice. In wild-type mice subjected to the Ang II infusion, cardiac hypertrophy developed after 2 weeks. In mice overexpressing human MR-1 (transgenic), however, cardiac hypertrophy was significantly greater than in wild-type mice as estimated by heart weight:body weight ratio, cardiomyocyte area, and echocardiographic measurements, as well as cardiac atrial natriuretic peptide and B-type natriuretic peptide mRNA and protein levels. Our further results showed that cardiac inflammation and fibrosis observed in wild-type Ang II mice were augmented in transgenic Ang II mice. Importantly, increased nuclear factor B activation was significantly increased higher in transgenic mice compared with wild-type mice after 2 weeks of Ang II infusion. In vitro experiments also revealed that overexpression of MR-1 enhanced Ang II-induced nuclear factor B activation, whereas downregulation of MR-1 blocked it in cardiac myocytes. In conclusion, our results suggest that MR-1 plays an aggravative role in the development of cardiac hypertrophy via activation of the nuclear factor B signaling pathway. Key Words: hypertrophy Ⅲ myocardium Ⅲ NF-B Ⅲ myofibrillogenesis regulator-1 Ⅲ fibrosis Ⅲ angiotensin II T he heart undergoes adaptive hypertrophic growth to augment cardiac output in response to a variety of pathological stimulations, including hypertension, myocardial infarction, pressure overload, and abnormalities in contractility and structure because of inherited gene mutations. 1,2 Although initial cardiac hypertrophy acts like an adaptive mechanism, prolonged and severe hypertrophy is a risk factor for arrhythmias, sudden death, and heart failure. Because cardiac hypertrophy is a highly complex disorder that results from an interaction of genetic, physiological, and environmental factors, many genes and their products participated in its pathogenesis through different pathways. 1,2 Therefore, the discovery and functional clarification of cardiac hypertrophyrelated novel human genes are important for understanding the molecular mechanisms underlying cardiac hypertrophy.Myofibrillogenesis regulator-1 (MR-1) was identified from a human skeletal muscle cDNA library, which encodes a protein of 142 amino acids with a hydrophobic transmembrane structure from 75 to 92 amino acids. 3 MR-1 protein is mainly located on the nucleic membrane and, to a lesser extent, in the cytoplasm. Northern blot and serial analysis of gene expression revealed that the transcription level of MR-1 in human tissues is especially high in myocardium and skeletal muscle. 3 Yeast 2-hybrid screening and in vitro glutathione S-transf...

Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells

“…5,6 Moreover, AngII given exogenously to rodents has been shown to result in cellular changes within the myocardium, hypertrophy and eventual fibrosis, similar to that seen in humans. 5,[7][8][9] Taken together, this evidence strongly supports a role for AngII in the development of myocardial fibrosis. The direct mechanisms responsible, and the effector cells involved, have yet to be fully characterized.…”

“…This theory has been supported by the identification of mononuclear cells, positive for macrophage markers, in the infiltrating cell population. 7,8,[11][12][13] Cell phenotypes, and marker expression, are dynamic and cells can alter their molecular expression to respond appropriately to stimuli in their environmental milieu. There is a circulating monocyte/macrophage precursor population that expresses specific markers for this cell type but are a phenotypically heterogeneous population.…”

“…This has led some investigators to suggest that these cells are of the monocyte/ macrophage lineage. 7,8,[11][12][13] One should note that cells that stain positive for monocyte/macrophage markers do not account for all the infiltrating cells. 7,8,11 This observation suggests a role for a yet to be described cell type.…”

Myocardial migration by fibroblast progenitor cells is blood pressure dependent in a model of angII myocardial fibrosis

“…7 Investigations in small animals have confirmed that AngII exposure can result in myocardial fibrosis. [8][9][10][11][12][13][14][15] Such experiments have supported a direct relationship between RAS activation via AngII and fibrosis. Animal models of fibrosis using AngII have proven very helpful in understanding some of the molecular events leading to the development of fibrosis.…”

Cellular FLICE-Inhibitory Protein Protects Against Cardiac Remodeling Induced by Angiotensin II in Mice

“…31,32 This study for the first time revealed that cFLIP blocks cardiac fibrosis in vivo and inhibits TGF-␤1-induced collagen synthesis in vitro. In an attempt to elucidate the mechanisms underlying the antifibrotic effect of cFLIP, we analyzed key components of TGF-␤1-Smad signaling, which is a crucial pathway in the regulation of fibrosis.…”