Enhanced Expression of Angiotensin II Type 2 Receptor, Inositol 1,4,5-Trisphosphate Receptor, and Protein Kinase Cε During Cardioprotection Induced by Angiotensin II Type 2 Receptor Blockade

Abstract

Abstract-We hypothesized that the cardioprotective effect of angiotensin II type 2 receptor (AT 2 R) blockade with PD 123,319 (PD) on the recovery of left ventricular (LV) mechanical function after ischemia/reperfusion (IR) in the isolated working rat heart is associated with the enhanced expression of AT 2 R protein and mRNA as well as an increase in inositol 1,4,5-trisphosphate type 2 receptor (IP 3 R) and protein kinase C⑀ (PKC⑀) proteins. We assessed AT 2 R, angiotensin II type 1 receptor (AT 1 R), IP 3 R, and PKC⑀ protein expression (Western blots) and AT 2 R mRNA levels (Northern blots) in myocardium from isolated working rat hearts that were subjected to global ischemia (30 minutes) followed by reperfusion (30 minutes). Groups of adult rat hearts (nϭ6) were exposed to no IR, Key Words: angiotensin II Ⅲ mRNA Ⅲ inositol Ⅲ protein kinases Ⅲ ischemia A ngiotensin II (Ang II), a key effector peptide of the renin-angiotensin system (RAS), plays an important role in the control of blood pressure and blood volume. 1 High Ang II concentrations, associated with upregulation of the RAS after ischemia/reperfusion (IR), myocardial infarction (MI), or heart failure, 2 appear to be cardiotoxic and promote injury. Although most cardiovascular effects of Ang II are normally considered to be mediated via Ang II type 1 receptors (AT 1 Rs), recent evidence suggests that in the long term, Ang II type 2 receptors (AT 2 Rs) inhibit growth, promote apoptosis, decrease cellular matrix, decrease blood pressure, dilate glomerular afferent arterioles, increase renal and vascular NO production, and decrease heart rate. 3 Upregulation of AT 2 Rs after chronic MI or in heart failure 4 -6 is thought to mediate ventricular remodeling. Chronic antagonistic interaction between AT 1 R and AT 2 R is thought to be important in vascular remodeling. 3 During chronic AT 1 R blockade, effects of increased Ang II (due to loss of negative feedback on the RAS 7 ) may be mediated by AT 2 R activation, thereby contributing to the cardioprotective effects. 8,9 The postulated mechanism involves kinin, NO, and cGMP signaling. 10 In the isolated Langendorff (nonworking) rat heart, AT 1 R blockade (produced either acutely or by prior shortterm pretreatment) was reported to improve recovery of left ventricular (LV) function after IR. 11 In the isolated working rat heart, acute AT 2 R blockade with PD 123,319 (PD) produced dramatic improvement of LV function after IR 12 ; however, AT 1 R/AT 2 R status was not determined.Recently, the inositol 1,4,5-trisphosphate (IP 3 ) type 2 receptor (IP 3 R) was implicated in calcium regulation in myocytes, 13,14 protein kinase C (PKC) was associated with AT 2 R-mediated effects, 15 and PKC⑀ was associated with cardioprotection involving NO. 16 Thus, we hypothesized that the cardioprotective effect of the AT 2 R blockade during IR in the isolated working rat heart is associated with an increase in AT 2 R mRNA and protein expression as well as with an increase in IP 3 R 13,14 and PKC⑀ 15,16 proteins but with no change in A...

<b>Downregulation of Peroxisme Proliferator Activated Receptor Gamma Co-Activator 1&alpha; in Diabetic Rats</b>

“…[12][13][14] Although the impact of angiotensin II type I (AT1) receptor blocker therapy on improving CHF, LV function, and clinical outcomes has been consistently demonstrated in various clinical settings, [23][24][25][26][27][28][29] the mechanism of action through which these drugs improve CHF and LV function has not been fully elucidated. 27,30,31) The primary finding in this study was that the losartan and not the simvastatin therapy significantly enhanced the PGC-1α gene expression and improved LV function. Two recent studies 32,33) reported that some AT1 receptor blockers may act as partial agonists of peroxisome proliferator activated receptor-γ.…”

Angiotensin II Type 2 Receptor Is Essential for Left Ventricular Hypertrophy and Cardiac Fibrosis in Chronic Angiotensin II–Induced Hypertension

“…Various studies suggest that AT 2 is inhibitory to cell growth and perhaps even related to the induction of programmed cell death. Conversely, Xu et al 27 recently demonstrated that the cardioprotective effect of acute treatment with an AT 2 antagonist on LV functional recovery after ischemia/reperfusion in the isolated working rat heart is specifically due to AT 2 blockade. Furthermore, Mifune et al 11 reported that AT 2 stimulation increased collagen synthesis in vascular smooth muscle via a G␣ i -mediated mechanism.…”

Upregulation of Arginase by H2O2Impairs Endothelium-Dependent Nitric Oxide-Mediated Dilation of Coronary Arterioles

“…Although it is somewhat surprising that a significant arginase induction in coronary microvessels can be achieved within such a short period (ie, 60 minutes) of exposure to H 2 O 2 , previous studies have shown that pharmacological and pathophysiological stimulations can alter the expression of mRNA and/or protein within 60 minutes. [51][52][53][54] Interestingly, our recent studies demonstrated that vascular arginase I was upregulated leading to the impaired NO-mediated dilation in the porcine heart subjected to either chronic hypertension (8 weeks) 55 or an acute episode of ischemiareperfusion. 56 Because ROS, including H 2 O 2 , play an important role in the vascular dysfunction in hypertension 5 and ischemia-reperfusion injury, 7 it is speculated that H 2 O 2 may be the molecule that triggers the overexpression of vascular arginase and consequently leads to the impairment of NOS-mediated vascular function under these pathophysiological conditions.…”