Plin5/p-Plin5 Guards Diabetic CMECs by Regulating FFAs Metabolism Bidirectionally

Area of Science:

• Cardiovascular Biology
• Metabolic Diseases
• Cellular Physiology

Background:

• Hyper-free fatty acidemia (HFFA) negatively impacts cardiac capillaries and is linked to type 2 diabetes mellitus (T2DM).
• Perilipin 5 (Plin5) is known to regulate free fatty acid (FFA) metabolism in oxidative tissues.
• The specific role of Plin5 in cardiac microvascular endothelial cells (CMECs) during T2DM-HFFA remains unclear.

Purpose of the Study:

• To investigate the role of Perilipin 5 (Plin5) in cardiac microvascular endothelial cells (CMECs) under conditions of type 2 diabetes mellitus (T2DM) and hyper-free fatty acidemia (HFFA).
• To elucidate how Plin5's phosphorylation state influences FFA metabolism and cell survival in diabetic CMECs.

Main Methods:

• T2DM models were established in wild-type and Plin5-deficient mice.
• CMECs were treated with high glucose and high FFAs, with Plin5 phosphorylation induced by isoproterenol and expression reduced via siRNA.
• Cardiac function, apoptosis, microvascular integrity, lipid metabolism, oxidative stress markers, and nitric oxide production were assessed.

Main Results:

• In CMECs, high FFAs exacerbated high glucose-induced injury and activated Plin5.
• Plin5 deficiency in T2DM-HFFA mice led to reduced capillary density and impaired cardiac function.
• Plin5 modulation in CMECs affected lipid droplet content, FFA levels, mitochondrial beta-oxidation, ROS generation, and endothelial nitric oxide synthase (eNOS) activity, impacting cell survival.

Conclusions:

• Plin5 plays a protective role in diabetic CMECs by maintaining lipid balance.
• Bidirectional regulation of FFA metabolism by Plin5, through its non-phosphorylated and phosphorylated states, is essential for CMEC survival.
• Plin5 is a key regulator of cardiac microvascular function in the context of T2DM-HFFA.