Leptin signalling reduces the severity of cardiac dysfunction and remodelling after chronic ischaemic injury

Smith

American Journal of Physiology-Regulatory, Integrative and Comp

et al. 2012

Although disruption of leptin signaling is associated with obesity as well as cardiac lipid accumulation and dysfunction, it has been difficult to separate the direct effects of leptin on the heart from those associated with the effects of leptin on body weight and fat mass. Using Cre-loxP recombinase technology, we developed tamoxifen-inducible, cardiomyocyte-specific leptin receptor-deficient mice to assess the role of leptin in regulating cardiac function. Cre recombinase activation in the heart resulted in transient reduction in left ventricular systolic function which recovered to normal levels by day 10. However, when cardiomyocyte leptin receptors were deleted in the setting of Cre recombinase-induced left ventricular dysfunction, irreversible lethal heart failure was observed in less than 10 days in all mice. Heart failure after leptin receptor deletion was associated with marked decreases of cardiac mitochondrial ATP, phosphorylated mammalian target of rapamycin (mTOR), and AMP-activated kinase (pAMPK). Our results demonstrate that specific deletion of cardiomyocyte leptin receptors, in the presence of increased Cre recombinase expression, causes lethal heart failure associated with decreased cardiac energy production. These observations indicate that leptin plays an important role in regulating cardiac function in the setting of cardiac stress caused by Cre-recombinase expression, likely through actions on cardiomyocyte energy metabolism.

Section: Discussionsupporting

confidence: 66%

Cardiomyocyte-specific deletion of leptin receptors causes lethal heart failure in Cre-recombinase-mediated cardiotoxicity

Smith

American Journal of Physiology-Regulatory, Integrative and Comp

et al. 2012

Cellular and Molecular Biology Letters

“…Numerous studies suggest that leptin is an important mediator of pathological cardiac remodeling [13,14,17,19,[21][22][23][24], which is characterized by cardiomyocyte hypertrophy and a disruption of the ECM resulting in increased collagen deposition [1,3]. Here we investigated the effect of leptin on regulation of myocardial matrix components, specifically MMP-2 activity, TIMP-1 expression and collagen-I/-III expression, in HL-1 cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Leptin regulates MMP-2, TIMP-1 and collagen synthesis via p38 MAPK in HL-1 murine cardiomyocytes

Schram

Girolamo

Madani

et al. 2010

Abbreviations used: AP-1 -activator protein-1; ATF-2 -activating transcription factor-2; ECM -extracellular matrix; HF-heart failure; LV -left ventricular; MAPK -mitogen activated protein kinase; MMP -matrix metalloproteinase; mRNA-messenger ribonucleic acid; PBS -phosphate buffered saline; PCR -polymerase chain reaction; TIMP-tissue inhibitor of metalloproteinase Abstract: A clear association between obesity and heart failure exists and a significant role for leptin, the product of the obese gene, has been suggested. One aspect of myocardial remodeling which characterizes heart failure is a disruption in the balance of extracellular matrix synthesis and degradation. Here we investigated the effects of leptin on matrix metalloproteinase (MMP) activity, tissue inhibitor of metalloproteinase (TIMP) expression, as well as collagen synthesis in HL-1 cardiac muscle cells. Gelatin zymographic analysis of MMP activity in conditioned media showed that leptin enhanced MMP-2 activity in a dose-and time-dependent manner. Leptin is known to stimulate phosphorylation of p38 MAPK in cardiac cells and utilization of the p38 MAPK inhibitor, SB203580, demonstrated that this kinase also plays a role in regulating several extracellular matrix components, such that inhibition of p38 MAPK signaling prevented the leptin-induced increase in MMP-2 activation. We also observed that leptin enhanced collagen synthesis determined by both proline incorporation and picrosirius red staining of conditioned media. Pro-collagen type-I and pro-collagen type-III expression, measured by real-time PCR and Western blotting were also increased by leptin, effects which were again attenuated by SB203580. In summary, these results demonstrate the potential for leptin to play a role in mediating myocardial ECM remodeling and that the p38 MAPK pathway plays an important role in mediating these effects.

“…It, therefore, remains one of the greatest challenges to global health and will continue to dominate global mortality trends in the future [1]. Myocardial infarct size remains one of the major prognostic factors in patients suffering from MI and myocardial reperfusion injury has been identified as a key determinant of myocardial infarct size in patients undergoing surgical or percutaneous coronary interventions (PCI) [69,99]. Other determinants include size and location of the area at risk, collateral blood flow, duration of ischemia and timing of the intervention to restore blood flow [69].…”

Section: Introductionmentioning

confidence: 99%

“…Myocardial infarct size remains one of the major prognostic factors in patients suffering from MI and myocardial reperfusion injury has been identified as a key determinant of myocardial infarct size in patients undergoing surgical or percutaneous coronary interventions (PCI) [69,99]. Other determinants include size and location of the area at risk, collateral blood flow, duration of ischemia and timing of the intervention to restore blood flow [69]. Other determinants of infarct size are the duration of ischaemia and although a period during which complete coronary occlusion results in reversible injury, this is about 30-40 min in humans [34].…”

Section: Introductionmentioning

confidence: 99%

Understanding STAT3 signaling in cardiac ischemia

et al. 2016

Cardiovascular disease is the leading cause of death worldwide. It remains one of the greatest challenges to global health and will continue to dominate mortality trends in the future. Acute myocardial infarction results in 7.4 million deaths globally per annum. Current management strategies are centered on restoration of coronary blood flow via percutaneous coronary intervention, coronary artery bypass grafting and administration of anti-platelet agents. Such myocardial reperfusion accounts for 40-50 % of the final infarct size in most cases. Signaling transducer and activator of transcription 3 (STAT3) has been shown to have cardioprotective effects via canonical and non-canonical activation and modulation of mitochondrial and transcriptional responses. A significant body of in vitro and in vivo evidence suggests that activation of the STAT3 signal transduction pathway results in a cardio protective response to ischemia and attempts have been made to modulate this with therapeutic effect. Not only is STAT3 important for cardiomyocyte function, but it also modulates the cardiac microenvironment and communicates with cardiac fibroblasts. To this end, we here review the current evidence supporting the manipulation of STAT3 for therapeutic benefit in cardiac ischemia and identify areas for future research.