Elevated myocardial SORBS2 and the underlying implications in left ventricular noncompaction cardiomyopathy

Area of Science:

• Cardiology
• Molecular Biology
• Genetics

Background:

• Left ventricular noncompaction cardiomyopathy (LVNC) is a hereditary heart condition.
• LVNC is characterized by excessive trabecular meshwork and deep intertrabecular recesses in the ventricular myocardium.
• Current management guidelines aim to prevent heart failure, but underlying mechanisms remain unclear.

Purpose of the Study:

• To investigate the role of Sorbin And SH3 Domain Containing 2 (SORBS2) in LVNC.
• To elucidate the molecular mechanism linking SORBS2 to heart failure in LVNC.

Main Methods:

• Protein mass spectrometry identified SORBS2 upregulation in LVNC hearts.
• In vivo studies involved AAV9 vector injection to overexpress SORBS2 in wild-type mice.
• In vitro studies utilized human embryonic stem cell-derived cardiomyocytes (hESC-CMs) overexpressing SORBS2.

Main Results:

• LVNC myocardial tissues showed elevated SORBS2, microtubule densification, and Junctophilin 2 (JP2) redistribution.
• SORBS2 interacts with β-tubulin, promoting microtubule polymerization.
• Overexpression of SORBS2 in mice led to cardiac dysfunction, T-tubule disorganization, and impaired Ca2+ handling.

Conclusions:

• SORBS2 interacts with β-tubulin, promoting microtubule densification.
• This process affects JP2 distribution and T-tubule structure.
• The SORBS2-mediated pathway is a potential contributor to heart failure in LVNC.