Cardiomyocyte-specific NHE1 overexpression confers protection against myocardial infarction during hyperglycemia

Acute hyperglycemia on admission is frequently observed during the early phase after acute myocardial infarction (MI), even without the history of diabetes mellitus. We previously reported that inhibiting Na+/H+ exchanger 1 (NHE1) activity post-MI may improve outcomes, but not in the setting of MI with acute hyperglycemia. However, the precise role of NHE1 in the pathophysiology of MI with acute hyperglycemia remains to be elucidated, and there are no effective strategies for its prevention or treatment. We analyzed 85 post-MI patients, identifying acute hyperglycemia (glucose > 7 mM) in non-diabetic individuals, linked to elevated BNP, CK-MB, and reduced plasma Na+. Using retrospective cohort studies and MI with acute hyperglycemia mouse models, we demonstrated that hyperglycemia exacerbates myocardial injury by reducing extracellular Na+, increasing intracellular Na+, and elevating pH, suggesting NHE1 activation as inferred from the observed intracellular pH (pHi) shift. Cardiomyocyte-specific NHE1 ablation or pharmacological inhibition worsened cardiac dysfunction and fibrosis in MI with acute hyperglycemia, while NHE1 overexpression conferred protection. RNA sequencing and drug screening identified accelerated NHE1 activation via 3% NaCl and lithospermic acid (LA) as a novel strategy to mitigate cardiomyocyte necroptosis, alleviating ischemic injury in MI and ischemia reperfusion models. Hypoxia-hyperglycemia and necroptosis induction models in NHE1-knockout, NHE1-overexpressing, and MLKL-overexpressing cardiomyocytes revealed that NHE1 activation, unlike its protective role in oxygen–glucose deprivation, promotes MLKL degradation via autophagosome-lysosomal pathways, reducing cardiomyocyte death. MLKL knockout and MLKL-NHE1 double knockout mice confirmed that MLKL ablation counteracts NHE1 inhibition’s detrimental effects. 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. NHE1 activation emerges as a novel therapeutic strategy to reduce infarct size and preserve cardiac function in hyperglycemia-associated myocardial infarction (MI). Accelerated NHE1 activation via lithospermic acid (LA) and 3% NaCl infusion offers a groundbreaking approach for managing MI with acute hyperglycemia. For the first time, we demonstrate that cardiomyocyte NHE1 exacerbates cardiac injury by mediating MLKL degradation during MI with acute hyperglycemia. These findings not only unveil promising candidates for clinical cardiovascular therapy but also provide new insights into the treatment of diverse MI subtypes.