Acute Humanin Therapy Attenuates Myocardial Ischemia and Reperfusion Injury in Mice

Abstract

Objective Humanin, an endogenous anti-apoptotic peptide, has previously been shown to protect against Alzheimer’s disease and a variety of cellular insults. We evaluated the effects of a potent analog of humanin, HNG, in an in vivo murine model of myocardial ischemia and reperfusion (MI-R). Methods Male C57BL6/J mice (8–10 week old) were subjected to 45 min of left coronary artery occlusion followed by 24 hr reperfusion. HNG or vehicle was administered intra-peritoneally one hour prior or at the time of reperfusion. The extent of myocardial infarction per area-at-risk was evaluated at 24 hrs using Evans Blue dye and 2,3,5 triphenyltetrazolium chloride (TTC) staining. Left ventricular (LV) function was evaluated at one week post ischemia using high-resolution, 2- D echocardiography (VisualSonics Vevo 770). Myocardial cell signaling pathways and apoptotic markers were assessed at various time points (0–24 hrs) following reperfusion. Cardiomyocyte survival and apoptosis in response to HNG were assessed in vitro. Results HNG reduced infarct size relative to the area-at-risk in a dose dependent fashion, with a maximal reduction at the dose of 2 mg/kg. HNG therapy enhanced LV ejection fraction and preserved post-ischemic LV dimensions (end-diastolic and end-systolic), resulting in improved cardiac function. Treatment with HNG significantly increased the expression of pAMPK and p-eNOS in the heart and attenuated Bax and Bcl-2 levels following MI-R. HNG improved cardiomyocyte survival and decreased apoptosis in response to daunorubicin in vitro. Conclusions These data show that HNG provides cardioprotection in a mouse model of MI-R potentially through activation of AMPK-eNOS mediated signaling and regulation of apoptotic factors. HNG may represent a novel agent for the treatment of acute myocardial infarction.

Overexpression of TIMP3 Protects Against Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Apoptosis Through ROS/Mapks Pathway

“…These results were also supported by the changes of apoptosis-related molecules through western blotting analysis. Bcl-2, Bax, Caspase-3 and Caspase-9 are known as apoptosis-related proteins, with Bcl-2 being an anti-apoptosis factor, while Bax, Caspase-3 and Caspase-9 as pro-apoptotic molecules [2]. We found that the ratio of Bax/Bcl-2, Cleaved Caspase-3 and Cleaved Caspase-9 expression were all increased after reperfusion, as compared to sham group, while these upregulation was significantly suppressed by TIMP3 overexpression.…”

“…Myocardial ischemia caused by coronary blockage underlies the majority of cardiovascular-related deaths [1, 2]. It is clinically presented as permanent and fierce retrosternal pain, resulting in myocardial infarction, shock, cardiac arrhythmia or heart failure [3, 4].…”

Central insulin‐like growth factor‐1 ( IGF ‐1) restores whole‐body insulin action in a model of age‐related insulin resistance and IGF ‐1 decline

“…Total MBH protein was extracted with a modified RIPA buffer, and protein content was determined using the BCA protein assay (Sigma, St. Louis, MO, USA) with BSA as a standard. Western blotting was performed similarly as described (Huffman et al ., 2008; Muzumdar et al ., 2010). In brief, 20 μg of total protein was loaded onto 4–15% Bis–Tris stain‐free gels and electrophoresed at 120 V constant for 90 min ( n  = 12 per group).…”

Structure of three Humanin peptides with different activities upon interaction with liposome

“…Humanin (HN), a 24 amino acid peptide (see Fig. 1 for the amino acid sequence), was discovered as a potential therapeutic agent against AD-related diseases [3][4][5][6][7][8][9][10][11][12] and functions against AD-unrelated diseases as well [13,14]. However, the neuroprotective mechanism of HN has been little understood [15].…”