Search

Fibroblast growth factor 21 (FGF21) is a metabolic hormone having anti-oxidative and anti-hypertrophic effects. However, the regulation of FGF21 expression during acute myocardial infarction (AMI) remains unclear. We tested blood samples from 50 patients with AMI and 43 patients with stable angina pectoris (sAP) for FGF21, fatty acid binding protein 4 (FABP4), a protein secreted from adipocytes in response to adrenergic lipolytic signal, and total and individual fatty acids. Compared with sAP patients, AMI patients had higher serum FGF21 levels on admission, which were significantly correlated with peak FABP4 and saturated fatty acids (SFAs) but not with peak levels of cardiac troponin T. In mice, myocardial ischemia rapidly induced FGF21 production by the heart, which accompanied activation of AMP-activated protein kinase (AMPK)-dependent pathway. Like AICAR, an activator of AMPK, catecholamines (norepinephrine and isoproterenol) and SFAs (palmitate and stearate) significantly increased FGF21 production and release by cardiac myocytes via AMPK activation. Recombinant FGF21 induced its own expression as well as members of down-stream targets of AMPK involved in metabolic homeostasis and mitochondrial biogenesis in cardiac myocytes. These findings suggest that adrenergic overdrive and resultant adipose tissue lipolysis induce cardiac AMPK-FGF21 feed-forward loop that potentially provides cardioprotection against ischemic damage.

Background: Acute myocardial infarction (AMI) induces marked activation of the sympathetic nervous system. Fatty acid binding protein 4 (FABP4) is not only an intracellular protein, but also a secreted adipokine that contributes to obesity-related metabolic complications. Here, we examined the role of serum FABP4 as a pathophysiological marker in patients with AMI., Methods and Results: We studied 106 patients presenting to the emergency unit with a final diagnosis of AMI, including 12 patients resuscitated from out-of-hospital cardiac arrest (OHCA) caused by ventricular fibrillation. FABP4 levels peaked on admission or just after percutaneous coronary intervention and declined thereafter. Regression analysis revealed no significant correlation between peak FABP4 and peak cardiac troponin T determined by Roche high-sensitive assays (hs-TnT). Notably, FABP4 levels were particularly elevated in AMI patients who were resuscitated from OHCA (median 130.2 ng/mL, interquartile range (IQR) 51.8-243.9 ng/mL) compared with those without OHCA (median 26.1 ng/ml, IQR 17.1-43.4 ng/mL), while hs-TnT levels on admission were not associated with OHCA. Immunohistochemistry of the human heart revealed that FABP4 is abundantly present in adipocytes within myocardial tissue and epicardial adipose tissue. An in vitro study using cultured adipocytes showed that FABP4 is released through a β3-adrenergic receptor (AR)-mediated mechanism., Conclusions: FABP4 levels were significantly elevated during the early hours after the onset of AMI and were robustly increased in OHCA survivors. Together with the finding that FABP4 is released from adipocytes via β3-AR-mediated lipolysis, our data provide a novel hypothesis that serum FABP4 may represent the adrenergic overdrive that accompanies acute cardiovascular disease, including AMI.

Rationale: Wound healing after myocardial infarction involves a highly regulated inflammatory response that is initiated by the appearance of neutrophils to clear out dead cells and matrix debris. Neutrophil infiltration is controlled by multiple secreted factors, including the master regulator transforming growth factor β (TGFβ). Broad inhibition of TGFβ early postinfarction has worsened post-myocardial infarction remodeling; however, this signaling displays potent cell specificity, and targeted suppression particularly in the myocyte could be beneficial., Objective: Our aims were to test the hypothesis that targeted suppression of myocyte TGFβ signaling ameliorates postinfarct remodeling and inflammatory modulation and to identify mechanisms by which this may be achieved., Methods and Results: Mice with TGFβ receptor-coupled signaling genetically suppressed only in cardiac myocytes (conditional TGFβ receptor 1 or 2 knockout) displayed marked declines in neutrophil recruitment and accompanying metalloproteinase 9 activation after infarction and were protected against early-onset mortality due to wall rupture. This is a cell-specific effect, because broader inhibition of TGFβ signaling led to 100% early mortality due to rupture. Rather than by altering fibrosis or reducing the generation of proinflammatory cytokines/chemokines, myocyte-selective TGFβ inhibition augmented the synthesis of a constellation of highly protective cardiokines. These included thrombospondin 4 with associated endoplasmic reticulum stress responses, interleukin-33, follistatin-like 1, and growth and differentiation factor 15, which is an inhibitor of neutrophil integrin activation and tissue migration., Conclusions: These data reveal a novel role of myocyte TGFβ signaling as a potent regulator of protective cardiokine and neutrophil-mediated infarct remodeling.

Aims: Sarco(endo)plasmic reticulum Ca²(+)-ATPase 2a (SERCA2a) transports Ca²(+) by consuming ATP produced by mitochondrial respiratory chain enzymes. Messenger RNA (mRNA) for these enzymes is transcribed by mitochondrial transcription factors A (TFAM) and B2 (TFB2M). This study examined whether TFAM and TFB2M coordinately regulate the transcription of the Serca2 gene and mitochondrial genes., Methods and Results: Nuclear localization of TFAM and TFB2M was demonstrated by immunostaining in rat neonatal cardiac myocytes. Chromatin immunoprecipitation assay and fluorescence correlation spectroscopy revealed that TFAM and TFB2M bind to the -122 to -114 nt and -122 to -117 nt regions of the rat Serca2 gene promoter, respectively. Mutation of these sites resulted in decreased Serca2 gene transcription. In a rat myocardial infarction model, Serca2a mRNA levels significantly correlated with those of Tfam (r = 0.54, P < 0.001) and Tfb2m (r = 0.73, P < 0.001). Overexpression of TFAM and TFB2M blocked hydrogen peroxide- and norepinephrine-induced decreases in Serca2a mRNA levels. In addition, overexpression of TFAM and TFB2M increased the mitochondrial DNA (mtDNA) copy number and mRNA levels of mitochondrial enzymes., Conclusion: Although TFAM and TFB2M are recognized as mtDNA-specific transcription factors, they also regulate transcription of nuclear DNA, i.e. the Serca2 gene. Our findings suggest a novel paradigm in which the transcription of genes for mitochondrial enzymes that produce ATP and the gene for SERCA2a that consumes ATP is coordinately regulated by the same transcription factors. This mechanism may contribute to maintaining proper cardiac function.

Reduced expression of the SERCA2 gene impairs the calcium-handling and contractile functions of the heart. We developed an SERCA2 gene transfer system using lentiviral vectors, and examined the long-term effect of SERCA2 gene transfer in the rat ischemic heart failure model. A lentiviral vector containing the SERCA2 gene was infused into a rat heart by hypothermic intracoronary delivery 2 weeks after myocardial infarction (MI). The transduction efficiency was approximately 40%. Six months after transduction, echocardiogram and pressure-volume measurements revealed that the SERCA2 gene transfer had significantly protected against left ventricular (LV) dilation, and had improved systolic and diastolic function, resulting in reduction in mortality rates. The brain natriuretic peptide mRNA level showed a significantly decrease and the phosphorylation level of serine residue of phospholamban (PLN) showed an increase in the Lenti-SERCA2-transduced heart. Further, DNA microarray analysis disclosed that SERCA2 gene transfer had increased cardioprotective gene expression and lowered the expression of genes that are known to exacerbate heart failure. The SERCA2 gene was successfully integrated into the host heart, induced favorable molecular remodeling, prevented LV geometrical remodeling, and improved the survival rate. These results suggest that a strategy to compensate for reduced SERCA2 gene expression by lentiviral vectors serves as a positive inotropic, lucitropic, and cardioprotective therapy for post-MI heart failure.

Introduction: Fibroblast growth factor 21 (FGF21) has originally been identified as a regulator of carbohydrate and fatty acid (FA) metabolism. Recent studies showed that FGF21 was synthesized by the heart and had an anti-hypertrophic role in mice. However, little is known whether and how FGF21 levels are regulated during acute myocardial infarction (AMI). Hypothesis: We hypothesize that FGF21 is released from the heart in response to metabolic alteration of the cardiac myocytes resulting from sympathetic overdrive during AMI. Methods and Results: We retrospectively tested blood samples drawn at hospitalization and first five days from 46 patients with AMI for FGF21, free fatty acids (FFA) and fatty acid binding protein 4 (FABP4), a protein derived from adipocytes in response to adrenergic overdrive. We also examined blood samples from 43 patients with stable angina pectoris (sAP). FGF21 levels were 4.7-fold higher in AMI patients than in sAP patients (p=0.0019). In AMI, FGF21 levels peaked on admission and declined thereafter. The peak of Troponin T, a cardiac damage marker, was observer after 9h of admission. Metabolic markers FABP4 and FFA showed similar kinetics with FGF21, suggesting that FGF21 level would be associated cardiac metabolic alteration in AMI. In fact, circulating FGF21 level was closely correlated with FABP4 and FFA (FABP4: r=0.77, FFA: r=0.83). Next, we assessed the mechanisms of inducible FGF21 expression using cultured neonatal rat cardiomyocytes. Stimulation of cultured cardiomyocytes with either norepinephrine or saturated fatty acid (FA) but not with unsaturated FA increased FGF21 protein expression and release. Interestingly, FGF21 was coordinately regulated with ATF4, sirtuin1 and phosphorylated AMP-activated protein kinase (AMPK), regulatory proteins induced by metabolic stress. Finally, AMPK activator AICAR induced FGF21 protein levels, and AMPK inhibitor Compound C abrogated an induction of FGF21 expressions in cardiomyocytes with norepinephrine or saturated FA stimulations. Conclusions: Our data suggest that FGF21 is released from the heart during AMI in response to adrenergic overdrive through the activation of AMPK pathway. [ABSTRACT FROM AUTHOR]