Cardiomyocyte overexpression of the α1A-adrenergic receptor in the rat phenocopies second but not first window preconditioning

Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1614-24. doi: 10.1152/ajpheart.01072.2011. Epub 2012 Feb 3.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Echocardiography
  • Gene Expression / physiology
  • Heart Rate / physiology
  • Hemodynamics / physiology
  • In Situ Nick-End Labeling
  • Ischemic Preconditioning, Myocardial*
  • Male
  • Microarray Analysis
  • Mitogen-Activated Protein Kinases / physiology
  • Myocardial Contraction / physiology
  • Myocardial Infarction / pathology
  • Myocardial Ischemia / physiopathology
  • Myocardium / metabolism
  • Myocytes, Cardiac / metabolism*
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II / biosynthesis
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / physiology
  • Oxygen Consumption / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Transgenic
  • Real-Time Polymerase Chain Reaction
  • Receptors, Adrenergic, alpha-1 / biosynthesis*
  • Receptors, Adrenergic, alpha-1 / genetics

Substances

  • Receptors, Adrenergic, alpha-1
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Mitogen-Activated Protein Kinases