Key result
Transgenic overexpression of JP2NT in mice attenuated pathological remodeling in response to cardiac stress, whereas loss of nuclear JP2NT function accelerated hypertrophy and heart failure.
Stress-induced proteolysis of JP2 liberates a nuclear fragment (JP2NT) that acts as a stress-adaptive transcription regulator to attenuate pathological remodeling in heart failure.
No immediate clinical implications; leaves open JP2NT as a therapeutic target pending human validation.
Junctophilin-2 (JP2) is a structural protein required for normal excitation-contraction (E-C) coupling. After cardiac stress, JP2 is cleaved by the calcium ion-dependent protease calpain, which disrupts the E-C coupling ultrastructural machinery and drives heart failure progression. We found that stress-induced proteolysis of JP2 liberates an N-terminal fragment (JP2NT) that translocates to the nucleus, binds to genomic DNA, and controls expression of a spectrum of genes in cardiomyocytes. Transgenic overexpression of JP2NT in mice modifies the transcriptional profile, resulting in attenuated pathological remodeling in response to cardiac stress. Conversely, loss of nuclear JP2NT function accelerates stress-induced development of hypertrophy and heart failure in mutant mice. These data reveal a self-protective mechanism in failing cardiomyocytes that transduce mechanical information (E-C uncoupling) into salutary transcriptional reprogramming in the stressed heart.
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Guo et al. (2018) studied Heart failure. Transgenic overexpression of JP2NT vs. Loss of nuclear JP2NT function / controls was evaluated on Pathological remodeling and development of hypertrophy and heart failure. Transgenic overexpression of JP2NT in mice attenuated pathological remodeling in response to cardiac stress, whereas loss of nuclear JP2NT function accelerated hypertrophy and heart failure.
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