Pressure Overload Induces Cardiac Hypertrophy in Angiotensin II Type 1A Receptor Knockout Mice

Abstract

Background-Many studies have suggested that the renin-angiotensin system plays an important role in the development of pressure overload-induced cardiac hypertrophy. Moreover, it has been reported that pressure overload-induced cardiac hypertrophy is completely prevented by ACE inhibitors in vivo and that the stored angiotensin II (Ang II) is released from cardiac myocytes in response to mechanical stretch and induces cardiomyocyte hypertrophy through the Ang II type 1 receptor (AT 1 ) in vitro. These results suggest that the AT 1 -mediated signaling is critical for the development of mechanical stress-induced cardiac hypertrophy. Methods and Results-To determine whether AT 1 -mediated signaling is indispensable for the development of pressure overload-induced cardiac hypertrophy, pressure overload was produced by constricting the abdominal aorta of AT 1A knockout (KO) mice. Quantitative reverse transcriptase-polymerase chain reaction revealed that the cardiac AT 1 (probably AT 1B ) mRNA levels in AT 1A KO mice were Ͻ10% of those of wild-type (WT) mice and were not affected by pressure overload. Chronic treatment with subpressor doses of Ang II increased left ventricular mass in WT mice but not in KO mice. Pressure overload, however, fully induced cardiac hypertrophy in KO as well as WT mice. There were no significant differences between WT and KO mice in expression levels of fetal-type cardiac genes, in the left ventricular wall thickness and systolic function as revealed by the transthoracic echocardiogram, or in the histological changes such as myocyte hypertrophy and fibrosis.

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.…”

Pressure Overload Induces Severe Hypertrophy in Mice Treated With Cyclosporine, an Inhibitor of Calcineurin

“…For example, stretch of cultured neonatal cardiocytes results in local release of angiotensin II and activation of the AT 1 receptor, which appears to be required for the hypertrophic response in this in vitro system. 27 However, our laboratory 9 has shown that AT 1 receptor antagonism does not suppress hypertrophic growth in animals with aortic stenosis, and Harada et al 28 have demonstrated that hearts of mice with AT 1 receptor knockout exhibit a similar degree of hypertrophy as wild-type mice in response to aortic constriction. Kudoh et al 29 have also shown that mechanical stretch evokes hypertrophic responses in cardiocytes from AT 1 knockout mice.…”

Simvastatin prevents large blood pressure variability induced aggravation of cardiac hypertrophy in hypertensive rats by inhibiting RhoA/Ras–ERK pathways

“…36,37 Mechanical stress itself has a role in initiating hypertrophic responses in myocytes by activating multiple signaling pathways. 38,39 In contrast, the circulating and autocrine/paracrine humoral factors, such as angiotensin II, TGF-b and MCP-1, have been implicated in hypertensive myocardial fibrosis. 23,25,[40][41][42] Further research is necessary, to determine the mechanism by which simvastatin induces the different effects between myocyte hypertrophy and myocardial fibrosis in this model.…”