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

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Mitochondrial dysfunction is key in ventricular remodeling, but mechanisms are unclear.
• This study explores Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2)'s role in AMPK-mediated mitochondrial dysfunction and ventricular remodeling.

Purpose of the Study:

• To investigate the regulatory role of SHP2 in AMPK-mediated mitochondrial dysfunction.
• To elucidate SHP2's impact on ventricular remodeling.

Main Methods:

• Ventricular remodeling induced by Ang II/ISO in vitro and in vivo.
• SHP2 inhibition (SHP099) and knockdown (siSHP2) effects assessed.
• Interaction between AMPK and SHP2 confirmed via LC-MS/MS and Co-IP.
• SHP2 overexpression and AMPK activation (A769662) used for validation.

Main Results:

• SHP2 expression increased in remodeling models.
• SHP2 inhibition/knockdown improved cardiac function and mitochondrial health.
• SHP2 overexpression worsened remodeling; AMPK activation rescued this.
• SHP2 directly dephosphorylates AMPK at Thr172 via its PTP domain.

Conclusions:

• SHP2 dephosphorylates AMPK, driving mitochondrial dysfunction and ventricular remodeling.
• SHP2 is a potential therapeutic target for heart failure.