Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling

Area of Science:

• Cardiovascular Biology
• Molecular Cardiology
• Metabolic Signaling

Background:

• Pressure overload (PO) induces cardiac hypertrophy and heart failure, often accompanied by insulin resistance.
• Insulin receptor substrate 1 (IRS1) is activated by PO, but its specific role and that of IRS2 in left ventricular (LV) remodeling remain unclear.

Purpose of the Study:

• To investigate the divergent roles of IRS1 and IRS2 in the cardiac response to pressure overload.
• To elucidate the downstream signaling pathways involved in PO-induced LV remodeling.

Main Methods:

• Utilized cardiomyocyte-restricted IRS1 knockout (CIRS1KO) and IRS2 knockout (CIRS2KO) mouse models subjected to transverse aortic constriction (TAC) for PO.
• Analyzed cardiac function, hypertrophy, and signaling pathway activation (including Akt1/2) in response to TAC.
• Performed kinomic and gene expression profiling on failing human and mouse hearts.

Main Results:

• CIRS1KO hearts showed resistance to TAC-induced hypertrophy and heart failure, with attenuated Akt1 activation.
• CIRS2KO hearts exhibited exacerbated LV dysfunction after TAC, which was ameliorated by Akt1 haploinsufficiency.
• Human failing hearts displayed isoform-specific activation of IRS1 and Akt1, but not IRS2 and Akt2.
• IRS1 was linked to protein kinase G signaling and potentially a proinflammatory response.

Conclusions:

• IRS1 and Akt1 act as critical signaling nodes mediating LV remodeling during pressure overload.
• IRS1 signaling confers cardioprotection, whereas IRS2 signaling may worsen cardiac dysfunction under stress.
• These findings highlight isoform-specific roles of insulin receptor substrates in cardiac adaptation and failure.