Cardiomyocyte-specific NHE1 overexpression confers protection against myocardial infarction during hyperglycemia
Authors' conclusion
Activation of myocardial NHE1 promotes MLKL autophagic degradation, mitigating cardiomyocyte necroptosis and acute hyperglycemia-exacerbated MI, highlighting NHE1 as a hyperglycemia-dependent cardioprotective target. Moderate NHE1 activation may represent a novel therapeutic strategy for MI with acute hyperglycemia.
Study context
- Population
- Post-MI patients (acute hyperglycemia: glucose > 7 mM in non-diabetic individuals); Myocardial infarction (MI) with acute hyperglycemia mouse models
- Participants
- 85 post-MI patients
Methodological detailsretrospective cohort, mouse models, cardiomyocyte-specific NHE1 knockout and overexpression, RNA sequencing and drug screening
- Retrospective cohort
- Mouse models
- Cardiomyocyte-specific NHE1 knockout and overexpression
- RNA sequencing and drug screening
Main finding
As reported in the abstract
- Acute hyperglycemia in non-diabetic post-MI patients linked to elevated BNP, CK-MB and reduced plasma Na+
- Hyperglycemia exacerbates myocardial injury by reducing extracellular Na+, increasing intracellular Na+ and elevating pH, suggesting NHE1 activation
- Cardiomyocyte-specific NHE1 ablation or pharmacological inhibition worsened cardiac dysfunction and fibrosis in MI with acute hyperglycemia; NHE1 overexpression conferred protection
- Accelerated NHE1 activation via 3% NaCl and lithospermic acid mitigated cardiomyocyte necroptosis, alleviating ischemic injury in MI and ischemia reperfusion models
- NHE1 activation promotes MLKL degradation via autophagosome-lysosomal pathways, reducing cardiomyocyte death
- MLKL ablation counteracts the detrimental effects of NHE1 inhibition
Original publication
Cardiomyocyte-specific NHE1 overexpression confers protection against myocardial infarction during hyperglycemia. Cardiovasc Diabetol. Published 26 April 2025. doi:10.
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