Inhibiting SHP2 improves ventricular remodeling by restoring AMPK phosphorylation and mitochondrial homeostasis

Although mitochondrial dysfunction is an established hallmark of ventricular remodeling, the molecular mechanisms governing this process remain incompletely characterized. This study systematically investigates the regulatory role of Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) in AMPK-mediated mitochondrial dysfunction and its pathological consequences in ventricular remodeling.

Ventricular remodeling was induced by angiotensin II (Ang II) or isoproterenol (ISO) in vivo and in vitro, with assessment of hypertrophy and fibrosis using echocardiography, molecular analyses and histopathology. Bulk RNA-seq demonstrated that SHP099, an SHP2 inhibitor, modulated the AMPK pathway. LC-MS/MS and Co-IP confirmed the interaction between AMPK and SHP2. We constructed SHP2 mutant plasmids and employed AAV9-mediated cardiac SHP2 overexpression together with AMPK activator A769662 administration to validate the functional significance of this interaction.

SHP2 expression is upregulated in Ang II- or ISO-induced ventricular remodeling models. Both SHP099 (pharmacological inhibition) or siSHP2 (genetic knockdown) ameliorated cardiac hypertrophy and mitochondrial dysfunction, whereas SHP2 overexpression exacerbated these pathological changes. Mechanistically, SHP2 directly interacts with AMPK via its protein tyrosine phosphatase (PTP) domain at cysteine 459, dephosphorylating AMPK at Thr172. AAV9-mediated SHP2 overexpression aggravated ventricular remodeling, which was rescued by AMPK activator A769662.

This study demonstrates that SHP2 acts as a key phosphatase directly dephosphorylates AMPK, thereby triggering mitochondrial dysfunction and exacerbating ventricular remodeling. Our findings provide novel mechanistic insights into heart failure progression and highlight SHP2 as a potential therapeutic target for heart failure treatment.