Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK

Bussey, Carol T.; Thaung, H. P. Aye; Hughes, Gillian; Bahn, Andrew; Lamberts, Regis R.

doi:10.1113/ep087054

Cited by 5 publications

(5 citation statements)

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“…Phosphorylation of AMPK, an indicator of AMPK activity, increased in LV tissue of the diabetic animals compared with control animals, which corresponds to the increase observed in LV β 2 ‐AR expression (Thaung et al., ). Moreover, Bussey, Thaung, Hughes, Bahn, & Lamberts () recently showed a direct functional link between β‐AR responsiveness and AMPK signalling in the healthy and obese rat heart, although specific contributions of the β‐AR subtypes were not investigated. A limitation of our study is that the direct AMPK–β 2 ‐AR metabolic link was not assessed.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, Bussey, Thaung, Hughes, Bahn, & Lamberts (2018) recently showed a direct functional link between -AR responsiveness and AMPK signalling in the healthy and obese rat heart, although specific contributions of the -AR subtypes were not investigated. A limitation of our study is that the direct AMPK-2 -AR metabolic link was not assessed.…”

Section: Discussionmentioning

confidence: 99%

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β₂‐Adrenoceptors indirectly support impaired β₁‐adrenoceptor responsiveness in the isolated type 2 diabetic rat heart

Cook

Bussey

Fomison-Nurse

et al. 2019

Experimental Physiology

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New Findings What is the central question of this study?Are there specific contributions of β1‐ and β2‐adrenoceptor subtypes to the impaired β‐adrenoceptor responsiveness of the type 2 diabetic heart? What is the main finding and its importance?In hearts isolated from the Zucker diabetic fatty rat model of type 2 diabetes, we showed that the β1‐adrenoceptors are the main subtype to regulate heart rate, contraction and relaxation. Notably, the β2‐adrenoceptor subtype actions seem to support function in the diabetic heart indirectly. Abstract Impaired β‐adrenoceptor (β‐AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, but the independent contributions of β1‐ and β2‐AR subtypes to β‐AR‐associated cardiac dysfunction in diabetes are unknown. Our aim was to determine the specific β1‐ and β2‐AR responsiveness of heart rate (HR), contraction and relaxation in the diabetic heart. Isolated Langendorff‐perfused hearts of Zucker type 2 diabetic fatty (ZDF) rats were stimulated with the β‐AR agonist isoprenaline (1 × 10−11 to 3 × 10−8 mol l−1) with or without the selective β1‐AR antagonist CGP20712A (3 × 10−8 mol l−1) or the β2‐AR antagonist ICI‐118,551 (5 × 10−8 mol l−1), and HR, contraction and relaxation were measured. Diabetic hearts showed lower basal HR (non‐diabetic 216 ± 17 beats min−1 versus diabetic 151 ± 23 beats min−1, P < 0.05). However, the β‐AR‐induced increase in HR was similar and was completely blocked by the β1‐AR antagonist, but not by the β2‐AR antagonist. The β‐AR‐induced increase in contraction and acceleration of relaxation was impaired in diabetic hearts, completely blocked by the β1‐AR antagonist and partly impaired by the β2‐AR antagonist. Western blots revealed 41% higher phosphorylation levels of AMP kinase (AMPK), a key regulator of cardiac energy metabolism, in diabetic hearts (non‐diabetic 1.62 ± 0.19 a.u. versus diabetic 2.30 ± 0.25 a.u., P < 0.05). In conclusion, the β1‐AR is the main subtype regulating chronotropic, inotropic and lusitropic β‐AR responses in the healthy heart and the type 2 diabetic heart. The β2‐AR subtype indirectly supports the β1‐AR functional response in the diabetic heart. This suggests that β2‐ARs could be an indirect target to improve the function of the heart in type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

β₂‐Adrenoceptors indirectly support impaired β₁‐adrenoceptor responsiveness in the isolated type 2 diabetic rat heart

Cook

Bussey

Fomison-Nurse

et al. 2019

Experimental Physiology

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“…C1q/tumor necrosis factor-related protein 9 exhibited anti-myocardial lipotoxicity effects and attenuated cardiac hypertrophy, likely via activation of the LKB1–AMPK signaling [ 269 ]. A direct functional connection between AMPK signaling and β-adrenergic responsiveness exists in the heart, and AMPK might be a valuable target to recover the decreased β-adrenergic responsive in the heart of obesity [ 270 ]. Given that AMPK activation has beneficial metabolic consequences for obesity, AMPK has emerged as a promising therapeutic target for diabetic patients.…”

Section: Cardio-metabolic Diseasesmentioning

confidence: 99%

AMPK, Mitochondrial Function, and Cardiovascular Disease

Zou

2020

IJMS

149

101

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Adenosine monophosphate-activated protein kinase (AMPK) is in charge of numerous catabolic and anabolic signaling pathways to sustain appropriate intracellular adenosine triphosphate levels in response to energetic and/or cellular stress. In addition to its conventional roles as an intracellular energy switch or fuel gauge, emerging research has shown that AMPK is also a redox sensor and modulator, playing pivotal roles in maintaining cardiovascular processes and inhibiting disease progression. Pharmacological reagents, including statins, metformin, berberine, polyphenol, and resveratrol, all of which are widely used therapeutics for cardiovascular disorders, appear to deliver their protective/therapeutic effects partially via AMPK signaling modulation. The functions of AMPK during health and disease are far from clear. Accumulating studies have demonstrated crosstalk between AMPK and mitochondria, such as AMPK regulation of mitochondrial homeostasis and mitochondrial dysfunction causing abnormal AMPK activity. In this review, we begin with the description of AMPK structure and regulation, and then focus on the recent advances toward understanding how mitochondrial dysfunction controls AMPK and how AMPK, as a central mediator of the cellular response to energetic stress, maintains mitochondrial homeostasis. Finally, we systemically review how dysfunctional AMPK contributes to the initiation and progression of cardiovascular diseases via the impact on mitochondrial function.

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“…AMPK can increase fatty acid oxidation by increasing fatty acid uptake, increasing the expression of the fatty acid transporters, and by decreasing levels of malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase 1 [ 425 , 426 ] ( Figure 2 ). β-ARs have been shown to regulate AMPK in the heart [ 427 ] and the decrease in responsiveness in β-ARs during heart failure and its associated pathological remodeling has been linked to β-AR’s associated loss of AMPK signals [ 428 , 429 , 430 ]. As β 1 -ARs are downregulated in HF, β-AR blockers may reactivate AMPK pathways to shift metabolism to glucose utilization.…”

Section: Ars In Cardiac Metabolism and As Potential Therapeuticsmentioning

confidence: 99%

Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure

Perez

2021

IJMS

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The heart has a reduced capacity to generate sufficient energy when failing, resulting in an energy-starved condition with diminished functions. Studies have identified numerous changes in metabolic pathways in the failing heart that result in reduced oxidation of both glucose and fatty acid substrates, defects in mitochondrial functions and oxidative phosphorylation, and inefficient substrate utilization for the ATP that is produced. Recent early-phase clinical studies indicate that inhibitors of fatty acid oxidation and antioxidants that target the mitochondria may improve heart function during failure by increasing compensatory glucose oxidation. Adrenergic receptors (α1 and β) are a key sympathetic nervous system regulator that controls cardiac function. β-AR blockers are an established treatment for heart failure and α1A-AR agonists have potential therapeutic benefit. Besides regulating inotropy and chronotropy, α1- and β-adrenergic receptors also regulate metabolic functions in the heart that underlie many cardiac benefits. This review will highlight recent studies that describe how adrenergic receptor-mediated metabolic pathways may be able to restore cardiac energetics to non-failing levels that may offer promising therapeutic strategies.

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Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK

Cited by 5 publications

References 49 publications

β₂‐Adrenoceptors indirectly support impaired β₁‐adrenoceptor responsiveness in the isolated type 2 diabetic rat heart

β₂‐Adrenoceptors indirectly support impaired β₁‐adrenoceptor responsiveness in the isolated type 2 diabetic rat heart

AMPK, Mitochondrial Function, and Cardiovascular Disease

Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure

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Cardiac β‐adrenergic responsiveness of obese Zucker rats: The role of AMPK

Cited by 5 publications

References 49 publications

β2‐Adrenoceptors indirectly support impaired β1‐adrenoceptor responsiveness in the isolated type 2 diabetic rat heart

β2‐Adrenoceptors indirectly support impaired β1‐adrenoceptor responsiveness in the isolated type 2 diabetic rat heart

AMPK, Mitochondrial Function, and Cardiovascular Disease

Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure

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Product

Resources

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β₂‐Adrenoceptors indirectly support impaired β₁‐adrenoceptor responsiveness in the isolated type 2 diabetic rat heart

β₂‐Adrenoceptors indirectly support impaired β₁‐adrenoceptor responsiveness in the isolated type 2 diabetic rat heart