A Micropeptide that Inhibits Vascular Calcification via PKM2 Degradation
The vascular system is prone to calcification with advancing age. Cells in the vasculature inappropriately take on the features and behavior of the osteoblast cells responsible for building bone extracellular matrix. These errant vascular cells deposit calcium phosphate structures into vascular tissue, stiffening it. Calcification proceeds in parallel with atherosclerosis, the thickening of artery walls and generation of fatty plaques that obstruct vessels and ultimately rupture to cause a heart attack or stroke, but is an independent process that would cause dysfunction and mortality even if the causative mechanisms of atherosclerosis were eliminated.
Stiffening of vascular walls, however it occurs, whether by this process, other forms of damage and change in the extracellular matrix, or loss of responsiveness to cues for contraction and dilation in vascular smooth muscle, induces hypertension, among other issues. Perhaps more importantly, calcification of structures in the heart, such as the aortic valves, is ultimately fatal.
Present therapeutic options for calcification are limited. For example, a form of chelation using EDTA has been assessed in clinical trials, is readily available in clinics, but produces only modest benefits at best. Thus it is interesting to keep an eye on developments in this space. Today's open access paper describes a micropeptide therapy that can inhibit calcification processes, slowing vascular calcification meaningful in animal models. Slowing is a start, but effective reversal of age-related tissue calcification remains a unfulfilled goal.
Vascular calcification (VC) is not merely a passive mineralization process, rather, it is an active pathological event that is propelled by the osteogenic phenotypic transition of vascular smooth muscle cells (VSMCs). This transition is characterized by aberrant deposition of hydroxyapatite crystals within the vascular wall, leading to loss of vascular elasticity and increased risk of cardiovascular events. Despite advancements in clinical management strategies for VC, such as intensified dialysis regimens and phosphate binder therapies, current treatments remain insufficient to halt calcification progression, resulting in limited long-term prognostic improvement.
VSMCs undergo phenotypic switching from contractile to synthetic or inflammatory states under pathological stimulation, a critical initiating event in VC. Notably, this phenotypic transition is accompanied by marked metabolic reprogramming, characterized by a shift from oxidative phosphorylation to aerobic glycolysis, leading to lactate accumulation. Emerging evidence suggests that lactate not only induces synthetic phenotypic switching in VSMCs but also promotes vascular calcification through dual mechanisms: activating NR4A1-mediated mitochondrial fission and BNIP3-dependent mitophagy. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, catalyzes the irreversible conversion of phosphoenolpyruvate to pyruvate, directly regulating lactate biosynthesis. Strikingly, recent studies demonstrate that PKM2 inhibition preserves VSMC contractile phenotype and improves vascular homeostasis, suggesting its pivotal role in calcification-associated metabolic regulation.
In this study, we identified a 40-amino acid micropeptide, termed PKM2-associated micropeptide (PKM2 AP), which was highly expressed in patients with chronic kidney disease-related vascular calcification. PKM2 AP localized to both mitochondrial and cytoplasmic compartments and exhibited functional interactions with PKM2. Functional experiments demonstrated that overexpression of PKM2 AP both in vitro and in vivo attenuated the progression of vascular calcification. Mechanistically, PKM2 AP functioned as a molecular glue-like factor that facilitated the recruitment of the E3 ubiquitin ligase STUB1 to PKM2, thereby promoting PKM2 ubiquitination and degradation, ultimately suppressing aerobic glycolysis and lactate production in human aortic vascular smooth muscle cells (HAVSMCs). In vivo administration of PKM2 AP alleviates vascular calcification phenotypes in mouse models.