Cardioprotective Effects of Adiponectin-Stimulated Autophagy

Abstract

Cardiovascular diseases (CVDs), including heart failure, pose a significant economic and health burden worldwide. Current treatment strategies for heart failure are greatly limited, in that they mainly mitigate symptoms or delay further progression. In contrast, therapies aimed at proactively preventing the onset of heart failure could greatly improve outcomes. Adiponectin is an adipocyte-derived hormone that confers an array of cardioprotective effects. It exerts anti-inflammatory effects, improves metabolic function, mitigates endothelial cell dysfunction, and reduce cardiomyocyte cell death. Furthermore, it has gained increasing attention for its ability to activate autophagy, a conserved cellular pathway that facilitates the degradation and recycling of cell components. The disruption of autophagy has been linked to CVDs including heart failure. Additionally, growing evidence also points to specific forms of autophagy, namely mitophagy and lipophagy, as crucial adaptive responses in protection against CVDs. The protective effects of adiponectin, autophagy, mitophagy, and lipophagy against CVDs along with potential therapeutic implications will be discussed.

Keywords: Adiponectin; Autophagy; Cardiovascular diseases; Lipophagy; Mitophagy.

Fig. 1. Adiponectin confers cardioprotection via AdipoR1/2-AMPK signaling.

Adiponectin, existing in a monomeric, trimeric, or oligomeric form binds to AdipoR1/2. Upon binding, AMPK is activated, which dampens oxidative stress, atherosclerosis, apoptosis, fibrosis, and inflammation. AdipoR1/2, adiponectin receptors 1 or 2; AMPK, AMP-activated protein kinase; PGC1α, peroxisome proliferator-activated receptor-γ coactivator 1α; eNOS, endothelial nitric oxide synthase.

Fig. 2. Mechanisms via which adiponectin stimulates autophagy.

Adiponectin mediates activation of AMPK. AMPK phosphorylates ULK1 resulting in subsequent activation of the class III PI3K complex and initiating the formation of phagophore for autophagy. AMPK phosphorylates PINK1 and MFF to promote recruitment of autophagic machinery to mitochondria and activation of mitophagy. AMPK signaling also plays a role in mediating the autophagic degradation of lipids in a process termed lipophagy. AMPK, AMP-activated protein kinase; PI3K, phosphoinositide 3-kinase; PINK1, PTEN induced kinase 1; MFF, mitochondrial fission factor.

Fig. 3. Distinct roles of mitophagy in the cardiovascular setting.

AMPK signaling leads to phosphorylation and activation of ULK1 to facilitate protective autophagy. Mitophagy occurring through PINK1/Parkin or FUNDC1 is known to be protective against ischemic heart diseases. Upregulation of autophagy mediated through Beclin 1 is detrimental. Activation of mitophagy via NIX or BNIP3 is detrimental. AMPK, AMP-activated protein kinase; ULK1, unc-51 like autophagy activating kinase 1; PINK1, PTEN induced kinase 1; FUNDC1, FUN14 domain containing 1; BNIP3, Bcl-2 interacting protein 3.