RhoA/ROCK in Metabolic Syndrome

Metabolic syndrome (MetS) or insulin resistance syndrome, is a cluster of conditions that raises the risk of heart disease, type II diabetes, and stroke. These conditions include central obesity (i.e., excess body fat at the waist), hypertension, hyperglycemia, high blood triglycerides, and low HDL cholesterol. Those with three or more of these conditions may be diagnosed with MetS. MetS affects approximately one-third of adults in the United States. Pathogenesis of MetS is still not fully understood, though a variety of genetic, environmental, and lifestyle factors are thought to be involved.

Rho GTPases are a family of signaling proteins that play a key role in regulating the cytoskeleton. Activation of RhoA by GTP binding results in the activation of downstream effector proteins that mediate actin polymerization and stabilization and myosin II function¹. RhoA is involved in essential cellular processes, such as cytokinesis², stress fiber formation³, and smooth muscle cell contractility⁴, as well as several pathological processes, including tumor cell migration and invasion⁵ and cardiovascular diseases⁴. RhoA and its downstream effector proteins, Rho-associated protein kinases (ROCK1 and ROCK2), are also critical in MetS pathogenesis⁶. Elevated ROCK activity has been demonstrated in models of MetS conditions, including obesity, insulin resistance, elevated triglycerides, and hypertension^4,7. In the PBMCs of patients with type 2 diabetes mellitus, ROCK activity is elevated 420-570% compared to healthy controls⁸. Serum ROCK activity is also elevated in those diagnosed with MetS and correlated with waist circumference, fasting glucose, and triglyceride levels⁹. As a result, RhoA and ROCK have become attractive therapeutic targets for MetS treatment^10,11. One randomized controlled trial revealed that atorvastatin inhibits ROCK activity, which they suggest contributes to the anti-atherosclerotic benefit of statins¹². This newsletter will focus on recently identified roles for RhoA and ROCK signaling in the biological processes involved in MetS conditions.

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Also included in this newsletter:

• Actin and Microtubule Tools
• Related Publications