Protective Mechanism of Humanin Against Oxidative Stress in Aging-Related Cardiovascular Diseases

Abstract

Physiological reactive oxygen species (ROS) are important regulators of intercellular signal transduction. Oxidative and antioxidation systems maintain a dynamic balance under physiological conditions. Increases in ROS levels destroy the dynamic balance, leading to oxidative stress damage. Oxidative stress is involved in the pathogenesis of aging-related cardiovascular diseases (ACVD), such as atherosclerosis, myocardial infarction, and heart failure, by contributing to apoptosis, hypertrophy, and fibrosis. Oxidative phosphorylation in mitochondria is the main source of ROS. Increasing evidence demonstrates the relationship between ACVD and humanin (HN), an endogenous peptide encoded by mitochondrial DNA. HN protects cardiomyocytes, endothelial cells, and fibroblasts from oxidative stress, highlighting its protective role in atherosclerosis, ischemia-reperfusion injury, and heart failure. Herein, we reviewed the signaling pathways associated with the HN effects on redox signals, including Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor erythroid 2-related factor 2 (Nrf2), chaperone-mediated autophagy (CMA), c-jun NH2 terminal kinase (JNK)/p38 mitogen-activated protein kinase (p38 MAPK), adenosine monophosphate-activated protein kinase (AMPK), and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)-Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3). Furthermore, we discussed the relationship among HN, redox signaling pathways, and ACVD. Finally, we propose that HN may be a candidate drug for ACVD.

Keywords: aging-related cardiovascular diseases; humanin; metabolic abnormalities; oxidative stress; redox signaling pathways.

Figure 1

Regulation of HN expression under oxidative stress. HN levels in peripheral blood are regulated by IGF and IGFBP. IGFBP-3 is the main component of IGFBP in peripheral blood, with high affinity to HN. IGFBP-3 may transport HN through the blood–brain barrier (Blue dotted arrow), thereby reducing ROS and further protecting nerve cells. Growth hormone down-regulates HN levels in peripheral blood through the high expression of IGF-1. Mitochondrial stressors, such as serum deprivation and chemotherapeutic drugs, increase HN expressions. Anti-apoptotic factors decrease HN expressions. HN levels under oxidative stress may be regulated by increasing IGFBP-3 levels or inhibiting IGF-1 levels.

Figure 2

Regulation of HN on Keap1/Nrf2 signaling pathway under oxidative stress. HN promotes Keap1 degradation and release of Nrf2. Under stress conditions, HN inhibits the expression of Keap1, promotes the dissociation of Nrf2 and Keap1, activates the expression of antioxidant genes (SOD, CAD, HO-1, NQO1), and protects mitochondria from oxidative stress damage. Stress also triggers UPRmt, promotes the expression of antioxidant genes and the recovery of mitochondrial function, further promoting the formation of HN.

Figure 3

Regulation of HN on CMA under oxidative stress. Under oxidative stress, Hsc70 recognizes the oxidized protein (substrate), transports it to lysosomal membrane, and binds to LAMP-2 receptor on lysosomal membrane. The endogenous HN located in lysosomal membrane cytoplasmic assay stabilizes the binding of substrate and lysosome through Hsp90, and transports the substrate to lysosomal body with the assistance of Lys-Hsc70 to remove oxidized protein. Exogenous supplement of HNG enhances the binding of substrate and lysosome mediated by Hsp90, up-regulates CMA and further reduces oxidative stress damage. HN restores the activity of cathepsin D through FPRL1, promotes autophagy and reduces the production of ROS.

Figure 4

Regulation of HN on MAPKs, PI3K/AKT, and JAK2/STAT3 under oxidative stress. HN inhibits intracellular Ca2⁺ influx, inhibits ROS formation, activates MAPKs inhibitors, inhibits the activation of JNK and p38 MAPK, and reduces oxidative stress damage; HN activates the PI3K/Akt signaling pathway, which further activates the downstream JAK2/STAT3 signaling pathway, promotes the expression of antioxidant protein, reduces the level of ROS, and reduces the oxidative stress damage.

Figure 5

Regulation of HN on AMPK/mTOR under oxidative stress. HN up-regulates the phosphorylation of AMPK, activates eNOS, inhibits mTOR, NOX2 and NF-κB, to reduce the production of ROS, improve endothelial function.

Figure 6

Regulation of HN on redox system in ACVD. HN activates AMPK and PI3K/AKT, JAK2/STAT3 signaling pathways, induces CMA, promotes Nrf2 release, and inhibits JNK/p38MAPK pathway, inhibits oxidative stress damage and ACVD (inside the box: the red font represents the future research direction, the blue thick arrow represents the influence of HN on the five signal pathways, and other signs form a signal network).