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Published on: June 7, 2016
Increased AT(2)R protein expression but not increased apoptosis during cardioprotection induced by AT(1)R blockade
Rohit Moudgil1, Sorin Musat-Marcu, Yi Xu
1Department of Medicine, Division of Cardiology, University of Alberta, Edmonton, Alberta T6G 2R7, Canada.
Background:
The angiotensin II type 2 receptor (AT2R) is considered to be antigrowth and to mediate apoptosis in several cell types. Whether AT2R upregulation, associated with angiotensin II type 1 receptor (AT1R) blockade and cardioprotection after ischemia-reperfusion (IR), might not result in increased cardiomyocyte (CM) apoptosis has not been documented.
Objectives:
To determine whether increased AT2R protein expression, during AT1R blockade after acute IR, is associated with no increase in CM apoptosis.
Materials And Methods:
The recovery of left ventricular (LV) mechanical function after acute IR (30 min of ischemia, 40 min of reperfusion) was measured in isolated Langendorff rat hearts following pretreatment with the AT1R antagonist candesartan (CN) (CN 10 nmol/L) for 40 min before ischemia. The authors established with an initial dose-response curve using escalating concentrations of CN that 10 nmol/L abrogated vasoconstriction induced by angiotensin II (0.1 mol/L). AT1R and AT2R protein expression (Western immunoblot), CM apoptosis (terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end-labelling assay and nuclear morphology) and apoptotic markers (Bax, Bcl-2, caspase-3, p53) were assessed in LV tissue.
Results:
Compared with IR controls, CN improved peak systolic pressure, LV developed pressure and positive dp/dt, and increased AT2R (not AT1R) protein, but did not change the level of apoptosis or the expression of Bax, Bcl-2, caspase-3 or p53. CN also increased AT2R protein after ischemia alone but did not change CM apoptosis or expression of the markers.
Conclusions:
Increased AT2R protein expression during AT1R blockade after IR in the isolated Langendorff rat heart is associated with cardioprotection but no increase in CM apoptosis.
Insights
Angiotensin II type 2 receptor (AT2R) blockade during ischemia-reperfusion (IR) protects the heart without increasing cardiomyocyte apoptosis. This suggests AT2R upregulation offers cardioprotection post-IR.
Area of Science:
- Cardiovascular Research
- Molecular Cardiology
- Ischemia-Reperfusion Injury
Background:
- The angiotensin II type 2 receptor (AT2R) is generally considered antigrowth and pro-apoptotic.
- AT2R upregulation is observed following angiotensin II type 1 receptor (AT1R) blockade and is linked to cardioprotection after ischemia-reperfusion (IR).
- It remains undocumented whether this AT2R upregulation contributes to cardiomyocyte (CM) apoptosis.
Purpose of the Study:
- To investigate if increased AT2R protein expression, induced by AT1R blockade post-IR, is associated with a lack of increased CM apoptosis.
- To evaluate the impact of AT1R blockade on cardiac function and apoptosis markers after IR.
Main Methods:
- Isolated Langendorff rat hearts underwent acute IR (30 min ischemia, 40 min reperfusion) after pretreatment with candesartan (CN), an AT1R antagonist.
- Left ventricular mechanical function was assessed.
- AT1R and AT2R protein expression, CM apoptosis, and apoptotic markers (Bax, Bcl-2, caspase-3, p53) were quantified in LV tissue.
Main Results:
- Candesartan (CN) improved cardiac function (peak systolic pressure, LV developed pressure, +dp/dt) post-IR.
- CN significantly increased AT2R protein expression but not AT1R.
- No significant increase in CM apoptosis or changes in apoptotic markers (Bax, Bcl-2, caspase-3, p53) were observed with CN treatment.
- CN also increased AT2R protein after ischemia alone, without affecting CM apoptosis.
Conclusions:
- Increased AT2R protein expression following AT1R blockade in isolated rat hearts post-IR is linked to cardioprotection.
- This AT2R upregulation does not result in increased cardiomyocyte apoptosis.
- AT1R blockade with candesartan demonstrates a cardioprotective effect without inducing apoptosis.
