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The hypotensive effect of acute and chronic AMP-activated protein kinase activation in normal and hyperlipidemic mice
Fiona H Greig1, Marie-Ann Ewart1, Eilidh McNaughton1
1Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
Insights
Hyperlipidemia disrupts arterial AMP-activated protein kinase (AMPK) function, increasing blood pressure. AMPK activation with AICAR reversed these effects in mice, suggesting a potential therapeutic target for cardiovascular health.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Pharmacology
Background:
- AMP-activated protein kinase (AMPK) regulates cellular energy and is found in the arterial wall.
- AMPK activation lowers blood pressure, but its role in hyperlipidemia-induced hypertension is unclear.
Purpose of the Study:
- To investigate the impact of hyperlipidemia on arterial AMPK function and its response to activation.
- To determine if AMPK activation can ameliorate hypertension in hyperlipidemic conditions.
Main Methods:
- ApoE(-/-) mice on a high-fat diet were treated with the AMPK activator AICAR.
- Blood pressure was measured via carotid artery cannulation.
- Aortic tissue was analyzed for AMPK activity, phosphorylation, and in vitro vascular function.
Main Results:
- Hyperlipidemic ApoE(-/-) mice exhibited elevated mean arterial pressure, which was normalized by chronic AICAR treatment.
- Chronic AICAR treatment increased AMPK and acetyl-CoA carboxylase phosphorylation in normolipidemic mice but not in ApoE(-/-) mice.
- AMPK activation induced vasodilation and an anticontractile effect in aortic rings, an effect attenuated in ApoE(-/-) mice.
Conclusions:
- Hyperlipidemia dysregulates the arterial AMPK pathway, contributing to hypertension.
- AMPK activation can reverse hyperlipidemia-associated hypertension and vascular dysfunction, potentially by improving vessel compliance.
Abstract:
AMP-activated protein kinase (AMPK) is present in the arterial wall and is activated in response to cellular stressors that raise AMP relative to ADP/ATP. Activation of AMPK in vivo lowers blood pressure but the influence of hyperlipidemia on this response has not been studied. ApoE(-/-) mice on high fat diet for 6weeks and age-matched controls were treated with the AMPK activator, AICAR daily for two weeks. Under anesthesia, the carotid artery was cannulated for blood pressure measurements. Aortic tissue was removed for in vitro functional experiments and AMPK activity was measured in artery homogenates by Western blotting. ApoE(-/-) mice had significantly raised mean arterial pressure; chronic AICAR treatment normalized this but had no effect in normolipidemic mice, whereas acute administration of AICAR lowered mean arterial pressure in both groups. Chronic AICAR treatment increased phosphorylation of AMPK and its downstream target acetyl-CoA carboxylase in normolipidemic but not ApoE(-/-) mice. In aortic rings, AMPK activation induced vasodilation and an anticontractile effect, which was attenuated in ApoE(-/-) mice. This study demonstrates that hyperlipidemia dysregulates the AMPK pathway in the arterial wall but this effect can be reversed by AMPK activation, possibly through improving vessel compliance.
