Differential Participation of Angiotensin II Type 1 and 2 Receptors in the Regulation of Cardiac Cell Death Triggered by Angiotensin II

Abstract

Angiotensin II (Ang II) is an active peptide that controls systolic blood pressure and also exerts long-term effects on cardiovascular tissue structure, including cardiac hypertrophy and fibrosis. 1 Two major receptors exist for Ang II termed type 1 and type 2 receptors (AT 1 R and AT 2 R, respectively). 2 AT 1 R are predominantly coupled to Gq/11 and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT 1 -induced growth responses are mediated by transactivation of growth factor receptors. 2 The signaling pathways of AT 2 R include serine and tyrosine phosphatases, phospholipase A2, nitric oxide, and cyclic guanosine monophosphate. The AT 2 R counteracts several of the growth responses initiated by the AT1 and growth factor receptors. 2 AT 1 R mediates the established actions of Ang II, including vasoconstriction, aldosterone and vasopressin release, renal sodium reabsorption, increased collagen deposition, cell proliferation, and, importantly, cardiomyocyte hypertrophy. 1,2 Meanwhile AT 2 R function is less clear, but current theories support a role in opposing the AT 1 R actions. 3 AT 2 R is highly expressed in the fetus; however, after birth, its expression decreases. 2 Both AT 1 R and AT 2 R are expressed in adult human and rat heart, and they are upregulated in several cardiac pathologies. 4,5 The effects of Ang II in the heart are cell type-specific. Cardiomyocyte function is tightly regulated by Ang II, which acts in promoting cardiac hypertrophy. 6 However, Ang II also triggers apoptosis in neonatal cardiomyocytes. 7,8 Cardiac fibroblasts play a central role in the maintenance and remodeling of extracellular matrix (ECM) in the normal heart and injured heart. 9 Cultured cardiac fibroblasts undergo AT 1 Rdependent proliferation in response to Ang II, 6 and promotes net accumulation of fibrillar collagen and cardiac fibrosis in vivo, and their expression in cardiac fibroblasts far exceeds that in myocytes. 10 AT 2 R have been shown to lead to stimulation, inhibition, or not affect cardiac fibrosis. [11][12][13] Whether the up-regulation of AT 1 R or AT 2 R stimulates Ang II-dependent adult cardiac cell death remains unsolved. To study this problem, we ectopically expressed AT 1 R and AT 2 R in cultured adult cardiac fibroblasts (ACFs) and adult cardiomyocytes (ACMs), and we investigated the effect of Ang II on cardiac cell death and hypertrophy. Our data show that Ang II stimulated AT 1 R-dependent apoptosis in cultured ACFs, The first two authors contributed equally to the work. BackgroundThe angiotensin II (ang II) type 1 (aT 1 R) and type 2 (aT 2 R) receptors are increased in the heart following myocardial infarction and dilated cardiomyopathy, yet their contribution at a cellular level to compensation and/or failure remains controversial.

Gender differences in apoptotic signaling in heart failure due to volume overload

“…These data are consistent with a lesser degree of apoptosis in the female AV shunt rat. There are many triggers to induce apoptosis such as angiotensin II (Ang II)/Ang II type 1 receptor (AT 1 R); in fact, Ang II induced a significant increase in BAX protein where Bcl-2 was decreased [34,35]. Losartan and AT 1 receptor blocker alone or in combination with simvastatin blocked the increase in BAX and caused an increase in Bcl-2 [30].…”

AT2 Receptor Mediated Activation of the Tyrosine Phosphatase PTP1B Blocks Caveolin-1 Enhanced Migration, Invasion and Metastasis of Cancer Cells

“…MDA-MB-231 cells express high endogenous levels of CAV1 (Figure 1a), but they lack the AT2R. So, we overexpressed AT2R in these cells using an adenovirus encoding AT2R (AdNHA-AT2R), which contained a bicistronic vector that permits co-expression of both the angiotensin receptor coupled to an HA-tag and the green fluorescent protein (GFP) [24]. Adenovirus with a vector for GFP only was used as a control (Ad ctrl).…”

“…Adenoviruses encoding AT2R (Ad-NHA-AT2R) are bicistronic vectors that co-express both the angiotensin receptors and the green fluorescent protein (GFP) [24]. As a control, cells were transduced with the Ad ctrl adenovirus that drove the expression of the GFP protein under the control of the same promoter.…”

High Molecular Weight Fibroblast Growth Factor-2 in the Human Heart Is a Potential Target for Prevention of Cardiac Remodeling

“…Nevertheless, as shown here, AT-2R was also implicated in the Ang II-induced Hi-FGF-2 upregulation, and would be expected to sustain elevated Hi-FGF-2 expression even when AT-1R is blocked. The role of AT-2R in cardiac pathology remains insufficiently understood; it is generally believed that, unlike AT-1R, AT-2R has beneficial effects counteracting several of the effects triggered by AT-1R [50], [51]. On the other hand, there is some evidence that AT-2R may exert similar effects as AT-1R, by mediating left ventricular hypertrophy and fibrosis in Ang II-induced hypertensive disease[52].…”