Blocking Annexin A2 Restores Heart Cell Cleanup After Heart Attack

Heart attacks kill billions of cardiomyocytes, and the heart's ability to clear damaged mitochondria — a process called mitophagy — is critical to recovery. When mitophagy fails, oxidative stress accumulates, cells die, and the heart remodels toward failure. Understanding what disrupts mitophagy in the infarcted heart has been an open question.

This study from Wuhan University, published in Circulation, identifies Annexin A2 (ANXA2) as a key suppressor of cardiac mitophagy. The team found ANXA2 is highly upregulated in ischemic failing hearts in both mice and humans, and that circulating ANXA2 levels positively correlate with cardiac injury severity in acute MI patients.

Using cardiomyocyte-specific knockdown and overexpression models in mice and neonatal rat ventricular myocytes, the researchers showed that ANXA2 suppresses mitophagy by directly binding PHB2, a mitophagy receptor embedded in the inner mitochondrial membrane. This interaction blocks PHB2 from recruiting LC3B — a key autophagy mediator — and also promotes PHB2 degradation through K48-linked polyubiquitination driven by the E3 ligase TRIM29. The result is impaired mitochondrial quality control under hypoxic stress.

Knocking down ANXA2 in cardiomyocytes restored mitophagy, reduced oxidative stress, blunted inflammatory infiltration, decreased infarct size, and improved heart function. Conversely, ANXA2 overexpression worsened outcomes. Critically, PHB2 silencing abolished all protective effects of ANXA2 deficiency, confirming the ANXA2–PHB2–LC3B axis as the operative pathway.

While the mechanistic picture is compelling, the study relies on mouse and neonatal rat models. Translation to human therapies will require safe, cardiomyocyte-targeted ANXA2 inhibitors and validation in larger preclinical and clinical studies. Nonetheless, this research identifies a druggable posttranslational mechanism with real potential for cardioprotection.