Effects of progranulin on the pathological conditions in experimental myocardial infarction model

Abstract

Progranulin is a secreted growth factor associated with multiple physiological functions in ischemic pathophysiology. However, it is still not fully understood how progranulin is involved in ischemic lesion and cardiac remodeling after myocardial infarction (MI). In this study, we investigated the effects of progranulin on myocardial ischemia and reperfusion injury. We investigated progranulin expression using Western blotting and immunostaining after permanent left coronary artery (LCA) occlusion in mice. Infarct size and the number of infiltrating neutrophils were measured 24 h after permanent LCA occlusion. Recombinant mouse progranulin was administered before LCA occlusion. In addition, we evaluated cardiac function using cardiac catheterization and echocardiography, and fibrosis size by Masson's trichrome staining after myocardial ischemia/reperfusion in rabbits. Recombinant human progranulin was administered immediately after induction of reperfusion. Progranulin expression increased in the myocardial ischemic area 1, 3, and 5 days after permanent LCA occlusion in mice. The administration of recombinant mouse progranulin significantly attenuated infarct size and infiltrating neutrophils 24 h after permanent LCA occlusion in mice. We also found that administration of recombinant human progranulin ameliorated the deterioration of cardiac dysfunction and fibrosis after myocardial ischemia/reperfusion in rabbits. These findings suggest that progranulin may protect myocardial ischemia/reperfusion injury. Cardiovascular diseases (CVD) are disorders of the heart and blood vessels, and a leading cause of death worldwide despite therapeutic intervention 1. The worldwide prevalence of CVD is approximately 17.7 million people every year, and CVD accounts for 30% of global mortality 2. Acute myocardial infarction (AMI) in CVD leads to the sudden cardiac death and heart failure, which is a devastating complication 3. AMI is an event of myocardial necrosis by acute thrombotic obstructions of blood flow in coronary arteries. Rapid reperfusion of coronary arteries achieved by percutaneous coronary intervention (PCI) and thrombolysis benefits patients with AMI 4,5. However, there are several problems with current therapy. Myocardial ischemia/reperfusion (I/R) injury increases myocardial infarct size and decreases blood flow associated with microcirculatory disturbances 6-8. Enlargement of I/R injury from delayed reperfusion therapy increases the risk of subsequent developments of cardiac rupture and heart failure, in patients with AMI 7. In addition, these therapies and subsequent therapeutic interventions increase the mental and economic burden on patients 9,10. Therefore, it is important to elucidate the pathogenesis of myocardial I/R injury and explore novel therapeutic targets for AMI. Progranulin is a secreted growth factor associated with embryonic development 11 , wound healing 12 , and inflammation 13,14. Progranulin expression is observed in macrophages, neutrophils and skeletal myocytes 15,16 .

Progranulin Protects Against Airway Remodeling Through the Modulation of Autophagy via HMGB1 Suppression in House Dust Mite-Induced Chronic Asthma

“…8 PGRN has pleiotropic properties by participating inflammatory response, regeneration, cell cycle control, and tissue development. [9][10][11][12] Of interest, PGRN is recently regarded as a crucial regulator to prevent fibrotic process in different diseases, such as liver fibrosis, 13 myocardial infarction 14 and cutaneous wound healing. 15 But the effect of PGRN on house dust mite-induced airway remodeling is still elusive.…”

Administration of a Recombinant Secretory Leukocyte Protease Inhibitor Prevents Aortic Aneurysm Growth in Mice

“…PGRN, which is a growth factor also referred to as granulin epithelin precursor, plays a critical role in in ammation and wound repair, and also suppresses in ammation by binding the TNF-α receptor and interrupting TNF-α signaling [16]. In several studies, administration of recombinant PGRN ameliorated renal injury, in ammatory arthritis, myocardial infarction, and acute lung injury [16][17][18][19][20]. The results in the present study showed that rPGRN was less effective than rSLPI in attenuating AA growth in mice.…”

Progranulin deficiency exacerbates cardiac remodeling after myocardial infarction

“…Previous reports have shown that PGRN has protective effects on ischemic pathology in the brain and kidney 17,18 . We have also reported that administration of PGRN protects against cardiac injury after MI in mice and rabbits 19 . However, the role of endogenous PGRN in cardiac remodeling after MI remains unclear.…”