Cardiomyocyte overexpression of the α1A-adrenergic receptor in the rat phenocopies second but not first window preconditioning.
We examined α(1A)-adrenergic receptor (AR) mediation of preconditioning in a novel α(1A)-AR cardiac transgenic (TG) rat model (α(1A)-TG). Compared with nontransgenic littermates (NTLs), in conscious α(1A)-TG rats, heart rate was reduced, contractility [left ventricle (LV) +dP/dt, ejection fraction, end-systolic elastance] was significantly enhanced, and triple product (LV systolic wall stress × LV +dP/dt × heart rate) was unchanged. However, infarct size (IS)/area at risk (AAR) in response to ischemia-reperfusion (30 min coronary occlusion/3 h reperfusion) was reduced to 35 ± 4.6% in α(1A)-TGs vs. 52 ± 2.2% in NTLs (P < 0.05). Second window preconditioning reduced IS/AAR in NTLs to 29 ± 2.7% but did not afford further protection in α(1A)-TGs. In contrast, with first window preconditioning, IS/AAR was reduced to similar levels in both α(1A)-TGs (12 ± 1.4%) and NTLs (10 ± 1.1%). In untreated α(1A)-TGs, cardioprotection was associated with enhanced myocardial phosphorylated (p)-mitogen/extracellular signal-regulated kinase (MEK), p-extracellular signal-regulated kinase (ERK), and inducible nitric oxide synthase (iNOS) at the protein level, along with a 1.3-fold increase in total nitric oxide synthase activity like in second window preconditioning. Affymetrix microarrays revealed that few genes (4.6% of 3,172 upregulated; 8.8% of 3,498 downregulated) showed directionally similar changes in α(1A)-TGs vs. NTLs subjected to second window preconditioning. Thus, second, but not first, window cardioprotection is evident in α(1A)-TGs in the absence of ischemic preconditioning and is mediated by iNOS activation associated with MEK/ERK phosphorylation. Transcriptionally, however, second window preconditioning is considerably more complex than α(1A)-TG preconditioning, with the alteration of thousands of additional genes affording no further protection than that already available in α(1A)-TG rats.
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103, USA.
Xin
X
Zhao
Jiyeon
J
Park
David
D
Ho
Shumin
S
Gao
Lin
L
Yan
Hui
H
Ge
Siiri
S
Iismaa
Lin
L
Lin
Bin
B
Tian
Dorothy E
DE
Vatner
Robert M
RM
Graham
Stephen F
SF
Vatner
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004452:Echocardiography; D015870:Gene Expression / Q000502:physiology; D006339:Heart Rate / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology; D020287:In Situ Nick-End Labeling; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D046228:Microarray Analysis; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010101:Oxygen Consumption / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D018340:Receptors, Adrenergic, alpha-1 / Q000096:biosynthesis* / Q000235:genetics
D018340:Receptors, Adrenergic, alpha-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases