Diabetes Advances Cardiomyocyte Senescence Through Interfering Rnd3 Expression and Function

Area of Science:

• Cardiovascular Biology
• Cellular Senescence
• Diabetic Complications

Background:

• Rnd3, a Rho-GTPase, is linked to cardiovascular diseases, but its role in diabetes-induced cardiomyocyte senescence is unclear.
• Diabetic cardiomyopathy (DCM) is a significant complication of diabetes, characterized by impaired cardiac function and cellular changes.
• Aging increases susceptibility to cardiac dysfunction, with older rats exhibiting impaired cardiac function and elevated senescence markers.

Purpose of the Study:

• To investigate the role of Rnd3 in cardiomyocyte senescence and diabetic cardiomyopathy (DCM).
• To elucidate the molecular mechanisms underlying Rnd3 regulation and its impact on cardiac function in diabetes.
• To identify potential therapeutic targets for mitigating diabetes-induced heart aging and dysfunction.

Main Methods:

• Assessed Rnd3 expression in diabetic patients and Sprague Dawley (SD) rats of different ages.
• Induced cardiomyocyte senescence using high glucose (HG) conditions in vitro and in vivo.
• Utilized microRNA sequencing, AAV9 vectors for gene manipulation, and STAT3 inhibitors to explore signaling pathways.

Main Results:

• Rnd3 expression was reduced in diabetic patients and cardiomyocytes under HG conditions, exacerbating senescence.
• miR-103a-3p was identified as a key regulator, suppressing Rnd3 and promoting senescence; its inhibition alleviated HG-induced effects.
• Rnd3 deficiency worsened HG-induced STAT3 activation; Rnd3 interacted with p-STAT3, promoting its degradation and reducing senescence.

Conclusions:

• Diabetes induces cardiomyocyte senescence and cardiac dysfunction through the miR-103a-3p/Rnd3/STAT3 signaling pathway.
• Therapeutic strategies targeting this pathway, such as restoring Rnd3 or inhibiting miR-103a-3p, show promise for DCM.
• Rnd3 plays a protective role against diabetes-induced cardiac aging by regulating STAT3 activity.