Table 1. Representative publications demonstrating cardioprotective role of HIF-1α.
| Cardioprotective modality | Significant end-points | Species | Methods | References |
|---|---|---|---|---|
| Intermittent hypoxia induced delayed PC is lost in heterozygous HIF-1α knockout mice | Myocardial infarct size; cardiac function; kidney EPO mRNA expression; Plasma EPO levels | Rat & mouse | Systemic intermittent hypoxic PC (5 cycles of 6% O2 for 6′/ 21% O2 for 6′); global I/R injury (30′/2 h) in isolated perfused heart in a working mode; RT-PCR for EPO, EPOR, Glut-1, iNOS, and VEGF mRNA; plasma EPO levels; apoptosis assays | Cai et al, 200323 |
| CoCl2 (30 mg/kg) induced activation of HIF-1α induces delayed PC via an iNOS-dependent pathway | Myocardial infarct size; HIF-1α and AP-1 DNA binding activity | Mouse | DNA binding activity by EMSA; iNOS knockout; global I/R injury (20′/30′) in Langendorff isolated perfused heart model | Xi et al, 200417 |
| DMOG induced activation of HIF-1α induces delayed PC via an HO-1-dependent anti-inflammatory mechanism | Myocardial infarct size; HO-1 and HIF-1α protein expressions; serum IL-8 levels; myocardial PMN infiltration; HIF-1 activated anti-inflammatory parameters in HMEC in vitro | Rabbit | DMOG induced HIF-1α activation; inflammatuar markers in HMEC and myocardium; I/R injury (30′/180′) by coronary ligation in vivo | Ockaili et al, 200548 |
| Hypoxic PC and adenovirus mediated HIF-1α overexpression reduce I/R induced cardiac cell death by late phase PC | Mitochondrial function, cell viability and LDH levels for PC effect; VEGF, Glut-1, Glut-4, HSP70 and iNOS mRNA and endogenous HIF-1α protein expressions | Rat | HIF-1α overexpression by infection with recombinant adenoviral vectors; hypoxic PC (3 h/14 h) and simulated I/R injury (2 h/15 h) of cardiomyocytes; mRNA expressions by QPCR | Date et al, 200558 |
| Constitutive overexpression of HIF-1α in transgenic mice results in delayed cardioprotection | Myocardial infarct size; cardiac function; capillary density, HIF-1α, VEGF and iNOS expressions | Mouse | HIF-1α overexpression by transgenic mice; ischemia injury by coronary ligation in vivo; cardiac functional measurement by 2D/M-mode echocardiography; immun-histochemistry, Western blotting and Northernblotting for gene/protein expressions | Kido et al, 200562 |
| Normoxic activation of HIF-1 in hearts following in vivo PHD2 siRNA administration attenuates reperfusion injury via an iNOS-dependent pathway | Myocardial infarct size; cardiac functions; cardiac HIF-1α and iNOS protein expressions | Mouse | HIF-1 activation via siRNA-mediated PHD-2 gene silencing; iNOS knockout; I/R injury (30′/60′) in Langendorff isolated perfused heart model | Natarajan et al, 200653 |
| siRNA mediated HIF-1 activation induces cardioprotection via adiponectin in diabetic hearts | Myocardial infarct size; cardiac functions; HIF-1 binding to and transactivation of adiponectin promoter; endothelial, cardiac and white adipose tissue adiponectin mRNA expressions | Mouse | HIF-1 activation via siRNA-mediated PHD-2 gene silencing; HIF-1 binding to adiponectin by EMSA; Adiponectin expression by QPCR; I/R injury (30′/60′) in Langendorff isolated perfused heart model | Natarajan et al, 200855 |
| Deferoxamine directed upregulation of HIF-1α induces PC through improvement of cGMP signalling | Percentage and rate of cardiomyocyte shortenning; phosphorylation activity of cGMP | Rabbit | HIF-1α upregulation by deferoxamine (150 mg/kg for 2 days); cyclic GMP protein kinase activity by a protein phosphorylation assay; simulated I (15′ 95% N2-5% CO2)/R(30′) injury of cardiomyoctes | Luciano et al, 200850 |
| Isoflurane induces early pharmacological PC mediated by HIF-1α activation | Myocardial infarct size; CK-MB levels; HIF-1α protein expression and DNA binding | Rabbit | Isoflurane (1 MAC) and rapamycin (0.25 mg/kg) treatment; HIF-1α expression by WB; HIF-1α DNA binding by EMSA; regional I/R injury (40′/180′) by coronary ligation in vivo | Raphael et al, 200845 |
| Ischemic early window of PC is lost in heterozygous HIF-1α knockout mice | Myocardial infarct size; cardiac function; apoptosis; impaired mitochondrial ROS production, PTEN oxidation and AKT phosphorylation in heterozygous HIF-1α knockout mice | Mouse | Ischemic PC (I/R for 10′/5′ or 2 cycles of I/R for 5′/5′); global I/R injury (30′/45′) in Langendorff isolated perfused heart model; Immunblotting for PTEN and AKT; apoptosis assays; mitochondrial ROS production | Cai et al, 200833 |
| HIF-1 has a central role in ischemic PC via transcriptional activation of purinergic signaling pathways | Myocardial infarct size; cardiac protein expression and nuclear translocation of HIF-1α PHD-1, -2, -3, and adenosine receptor transcript and protein levels; plasma troponin I levels; cardiac adenosine levels | Mouse | In vivo siRNA repression of cardiac HIF-1α tissue adenosine levels via HPLC; immunhistochemistry, transcriptional analysis and Western blotting of HIF-1α DMOG treatment (1 mg/mouse, ip); ischemic in situ PC (4 cycles of I/R for 5′/5′); I/R injury (60′/120′) by in vivo coronary ligation | Eckle et al, 200834 |
| Deferoxamine and CPX directed upregulation of HIF-1α induces PC by improved contractile and calcium handling responses to inotropic agents | Percentage and rate of cardiomyocyte shortenning; parameters of intracellular Ca2+ transient | Rabbit | HIF-1α upregulation by deferoxamine (150 mg/kg for 2 days) and CPX (50 mg/kg for 2 days); measurements of intracellular Ca2+ transients; simulated I (15′ 95% N2-5% CO2)/R(30′) injury of cardiomyocytes | Tan et al, 200951 |
| The upregulation of HIF-1α during hypoxic preconditioning by inhibition of miR-199a | miR-199a down-regulation and HIF-1α and Sirt1 upregulations during hypoxia; miR-199 inhibition of HIF-1α and Sirt1; mitochondrial integrity and longevity of cardiac cells | Rat | Adult and neonatal cardiomyocyte cell culture; Simulated hypoxic PC (4 cycles of 1 h hypoxia 1 h reoxygenation); Northern and Western Blotting and immunhistochemistry for the expressions of several RNAs and proteins; caspase activity and mitochondrial function | Rane et al, 200961 |
| HIF-1α and HO-1 gene therapy to the skeletal muscle created remote late cardioprotection against I/R injury | Myocardial infarct size; cardiac function; expression of HIF-1α and HO-1 in the skeletal muscle; HO-1 activity | Mouse | HIF-1α and HO-1 gene delivery to skeletal muscle; Immunblotting for expression of skeletal muscle, heart, spleen and serum proteins; global I/R injury (40′/60′) in Langendorff isolated perfused heart model | Czibik et al, 200959 |
| Mild exercise training induces cardioprotection by few significant genes including HIF-1α | Myocardial infarct size; caveolin 3, enolase 2 and HIF-1α expressions | Rat | Mild intensity training on a treadmill; gene expression profile in left ventricle by Affymetrix; real-time PCR expression of the genes; Immunohistochemistry and Western blotting; ischemia/reperfusion injury (30′/90′) by coronary ligation in vivo | Giusti et al, 200966 |
| Viable HIF-P4H-2 hypomorphic mouse hearts are protected against I/R injury by chronic stabilization of HIF-1α and HIF-2α and by induction of genes in glucose metabolism, cardiac function and blood pressure | LDH release; cardiac function; coronary flow rate; Hif-p4h-2 mRNA and protein expression in several tissues; cardiac upregulation of HIF targeted genes; cardiac energy metabolite levels | Mouse | Generation of Hif-p4h-2gt/gt mice; Q-PCR and microarray analysis of several genes; Western blotting for HIF-1α, HIF-2α, and HIF-P4H-2, histologic analysis of angiogenesis; β-Galactosidse activity; global I/R injury (20′/45′) in Langendorff isolated perfused heart model; Metabolite assays | Hyvarinen et al, 201064 |
| Chronic post-myocardial infarction oral treatment with a novel selective PHD inhibitor-GSK360A (30 mg/kg/day for 28 days) improves long-term ventricular function, remodeling, and vascularity | Circulating levels of EPO and hemoglobin; HO-1 expression in heart and skeletal muscle; left ventricular ejection fraction and chamber dilation; lung weight; microvascular density in peri-infarct region; survival rate | Rat | Development of GSK360A — a potent inhibitor of PHD (PHD1>PHD2=PHD3) capable of activating the HIF-1α pathway in various types of cells; Western blotting for HO-1 expression; in vivo rat model of heart failure induced by ligation of left anterior descending coronary artery; histologic analysis of angiogenesis | Bao et al, 201052 |
Abbreviations: EPO: Erythropoietin; EPOR: Erythropoietin receptor; Glut-1: Glucose transporter-1; iNOS: Inducible nitric oxide synthase; AP-1: Activating protein-1; DMOG: Dimethyloxalylglycine; HO-1: Hemoxygenase-1; HMEC: human microvascular endothelial cel line; I/R: Ischemia/Reperfusion; VEGF: Vascular endothelial growth factor; PC: Preconditioning; EMSA: Electrophoretic mobility shift assay; QPCR: Quantitative polymerase chain reaction; CPX: Ciclopirox olamine; MAC: Minimal alveolar concentration; CK-MB: Creatinin kinase-MB; WB: Western blotting; PHD: Prolyl-hydroxylase; PTEN: Phosphatase and tensin homologue; AKT: Protein kinase B; MicroRNA-199a: MiR-199a; Sirt1: Sirtuin1; HIF-P4H-2: HIF prolyl 4-hydroxylase-2.