Dual Modulation of Cell Survival and Cell Death by β2-Adrenergic Gi and Gs Signaling in Adult Mouse Cardiac Myocytes

Abstract

There is considerable debate about the choice of intravenous platelet glycoprotein IIb/IIIa inhibitors for percutaneous coronary intervention, after a meta-analysis of 7 trials and 16,770 patients has shown a 38% reduction in death or non-fatal MI 30 days after the index procedure. At 149 hospitals in 18 countries throughout North America, Europe and Australia, 4810 patients were randomized between 12/30/99 and 8/25/00 and treated with either tirofiban or abciximab on a double-blind, double dummy basis. Clopidogrel and aspirin were administered preprocedurally, along with a 70 U/kg intravenous heparin bolus. The dose of tirofiban was 10 mcg/kg bolus and 0.15 mcg/kg/min infusion for 18 -24 hrs; for abciximab it was 0.25 mcg/kg bolus and 0.125 mcg/kg/min (max 10 mcg/min) infusion. Patients qualified by having suitable anatomy for "intent-to-stent" lesions addressed by percutaneous revascularization, and were not with evolving ST-elevation MI or with serum creatinine Ͼ2.5 mg/dl. The primary endpoint is 30 death or non-fatal MI and the trial has Ͼ80% power to determine non-inferiority for tirofiban with an expected event rate in the control (abciximab) group of 5.3% based on the EPISTENT trial. The primary endpoint data will be presented along with the key subgroups such as diabetics. Follow-up data for the trial to 1 year will also be performed. Late Breaking Science: Linking Genes to Function in the Heart and Vasculature BASIC ABSTRACTS Exogenous Hematopoietic Stem Cells Can Regenerate Infarcted MyocardiumDonald Orlic, Jan Kajstura, Stefano Chimenti, Baosheng Li, Stacie Anderson, David Bodine, James Pickel, Annarosa Leri, Bernardo Nadal-Ginard, Piero Anversa, New York Medical College, Valhalla, NY; NHGRI/NIH, Bethesda, MD To determine whether hematopoietic stem cells (HSC) can transform into cardiomyocytes with the potential to repair dead myocardium after infarction, Lin/c-kit I-II HSC were harvested from transgenic mice expressing green fluorescent protein (GFP) and injected in the region bordering the infarct, 3-5 hours after coronary artery occlusion in mice. A band of closely packed cells was identified 7 to 17 days later in nearly 50% of HSC injected hearts, between the endocardial and epicardial surface of the infarcted ventricle. This band occupied 50 75% of the damaged portion of the wall. c-kit/GFP positive HSC were found in the infarcted area shortly after coronary ligation and were still detectable at 7 days. c-kit stained HSC were not labeled by markers of myocytes, ␣-sarcomeric actin and myosin, endothelial cells, factor VIII, and smooth muscle cells, smooth muscle actin. The band of tissue included in the infarcted zone was constituted 75% by GFP, ␣-sarcomeric actin, myosin and ␣-actinin positive cardiac muscle cells. Other GFP-positive cell populations were endothelial cells and smooth muscle cells, organized in nascent capillary structures and arterioles. Proliferating myocytes were small with partially aligned myofibrils and resembled late fetal-neonatal cells. GFP-positive replicating myocytes, ...

Level of G protein–Coupled Receptor Kinase-2 Determines Myocardial Ischemia/Reperfusion Injury via Pro- and Anti-Apoptotic Mechanisms

“…Downstream of the β 1 AR, protein kinase A (PKA) activation9,37,38 and Ca 2+ /calmodulin-dependent kinase II (CamKII) activation39,40 are known stimulators of myocyte apoptosis. On the other hand, β 2 AR coupling to Gi leads to cell survival and reduced apoptosis 10,41. As shown in our current study, the βARKct-mediated protective phenotype can be reversed by blocking β 2 AR with the addition of ICI118,551 implying a β 2 AR-Gi-dependent mechanism in play following I/R that is enhanced when GRK2 is inhibited.…”

GRK2 as a novel gene therapy target in heart failure

“…β 2 ARs also mediate the effects of CAs on the heart, but in a qualitatively different manner from β 1 ARs, as they can also couple to the AC inhibitory G protein (Gi) [15,19]. This dual Gs/Gi coupling has been implicated in differential β 2 AR signaling specifically concerning myocyte apoptosis as β 2 AR-Gi is cardioprotective, while this doesn’t occur with the pro-apoptotic β 1 ARs [19–21]. …”

β2 AR Agonists in Treatment of Chronic Heart Failure: Long Path to Translation

“…Three major advances in research during the last decade on the single cardiomyocyte level have demonstrated distinctly different, even opposite functional roles of two βAR subtypes in regulating cardiac structure and function: ( 1 ) dual coupling of most β 2 AR to both G s and G i proteins in cardiomyocytes [32–34]; ( 2 ) a cardiac protective role of β 2 AR signaling in improving cardiac function and myocyte viability [35, 36]; ( 3 ) PKA-independent, CaMKII-mediated β 1 AR apoptotic and maladaptive remodeling signaling in the heart [37–39] (Fig. 1).…”