Oxytocin attenuates cardiac hypertrophy by improving cardiac glucose metabolism and regulating OXTR/JAK2/STAT3 axis

Abstract

Background

The progress of cardiac hypertrophy is modulated by JAK2/STAT3 signaling pathway. Cardiac glucose metabolism derangement exacerbates the progression of cardiac hypertrophy. Oxytocin (OT) has emerged as a significant hormone involved in cardiovascular homeostasis, especially in protecting against cardiac hypertrophy. The present study aims to explore whether the anti-hypertrophy effect of oxytocin is related to the JAK2/STAT3 signaling pathway and cardiac glucose metablism.

Methods

Cardiac hypertrophy model was induced by angiotensin II (Ang II) in H9c2 cells and in mice with or without oxytocin treatment. Changes in cardiac histopathology were evaluated by hematoxylin and eosin (H&E), Masson staining, and wheat germ agglutinin (WGA) staining. The hypertrophy-related genes and JAK2/STAT3 pathway signaling molecules were analyzed by qRT-PCR and western blotting. The levels of glucose, pyruvic acid, lactic acid, and lactate dehydrogenase activity in H9c2 cells using the corresponding assay kits.

Results

The results showed that OT inhibited hypertrophic and fibrotic changes. Furthermore, OT increased intracellular levels of glucose and pyruvic acid, and decreased lactate dehydrogenase activity and lactic acid levels. Mechanistically, Ang II decreased oxytocin receptors (OXTR) expression and facilitated JAK2 and STAT3 phosphorylation. OT treatment increased OXTR expression and blocked JAK2 and STAT3 phosphorylation The OXTR-specific siRNA-mediated depleted expression could abrogate OT-induced anti-hypertrophic effects in H9c2 cells following angiotensin II insult. However, the JAK2/STAT3 inhibitor AG490 rescued the protective effects of OT against cardiac hypertrophy under OXTR downregulation.

Conclusion

OT exerts its protective effects against cardiac hypertrophy by improving cardiac glucose metabolism and regulating OXTR/JAK2/STAT3 axis.