Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats

Xing, Wenjuan; Li, Youyou; Hf, Zhang; Mi, Chunjuan; Hou, Zuoxu; Quon, Michael J.; Gao, Feng

doi:10.1152/ajpheart.00290.2013

Cited by 36 publications

(36 citation statements)

References 35 publications

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“…Consistent with results in cardiomyocytes (30,106), lowering GRK2 levels in vascular endothelial cells increases NO bioavailability, which can lead to enhanced vasorelaxation, and this can protect against hypertension in mice (9,245). Beneficial effects of lowering GRK2 in endothelial cells also include improved insulin signaling as recently shown in spontaneously hypertensive rats (279) and in a mouse model of type 2 diabetes (244). These data coupled with vascular smooth muscle targeting support GRK2 inhibition, not only in heart failure, but for hypertension as well.…”

Section: Grk2 and Hypertensionsupporting

confidence: 79%

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

127

152

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G protein-coupled receptors (GPCRs) are important regulators of various cellular functions via activation of intracellular signaling events. Active GPCR signaling is shut down by GPCR kinases (GRKs) and subsequent β-arrestin-mediated mechanisms including phosphorylation, internalization, and either receptor degradation or resensitization. The seven-member GRK family varies in their structural composition, cellular localization, function, and mechanism of action (see sect. II). Here, we focus our attention on GRKs in particular canonical and novel roles of the GRKs found in the cardiovascular system (see sects. III and IV). Paramount to overall cardiac function is GPCR-mediated signaling provided by the adrenergic system. Overstimulation of the adrenergic system has been highly implicated in various etiologies of cardiovascular disease including hypertension and heart failure. GRKs acting downstream of heightened adrenergic signaling appear to be key players in cardiac homeostasis and disease progression, and herein we review the current data on GRKs related to cardiac disease and discuss their potential in the development of novel therapeutic strategies in cardiac diseases including heart failure.

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Section: Grk2 and Hypertensionsupporting

confidence: 79%

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Sato

Chuprun

Schwartz

et al. 2015

Physiological Reviews

127

152

View full text Add to dashboard Cite

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“…Besides, an increase in fructose intake leads to a decreased urinary salt excretion (141) . Insulin resistance could also contribute to high blood pressure and several studies in rats and human subjects suggest that the improvement in insulin sensitivity is able to prevent hypertension appearance (142)(143)(144)(145) . Long-term hyperinsulinaemia seems to induce a prolonged activation of the sympathetic nervous system leading to an increased production of catecholamine and vasoconstrictors such as endothelin I, angiotensin II and thromboxane A2, as well as a decreased production of vasodilators such as NO and prostacyclin 2, all of which lead to an impairment of endothelial function and therefore to hypertension (146) .…”

Section: Secondary Diseasesmentioning

confidence: 99%

Similarities and interactions between the ageing process and high chronic intake of added sugars

et al. 2017

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In our societies, the proportions of elderly people and of obese individuals are increasing. Both factors are associated with high health-related costs. During obesity, many authors suggest that it is a high chronic intake of added sugars (HCIAS) that triggers the shift towards pathology. However, the majority of studies were performed in young subjects and only a few were interested in the interaction with the ageing process. Our purpose was to discuss the metabolic effects of HCIAS, compare with the effects of ageing, and evaluate how deleterious the combined action of HCIAS and ageing could be. This effect of HCIAS seems mediated by fructose, targeting the liver first, which may lead to all subsequent metabolic alterations. The first basic alterations induced by fructose are increased oxidative stress, protein glycation, inflammation, dyslipidaemia and insulin resistance. These alterations are also present during the ageing process, and are closely related to each other, one leading to the other. These basic alterations are also involved in more complex syndromes, which are also favoured by HCIAS, and present during ageing. These include non-alcoholic fatty liver disease, hypertension, neurodegenerative diseases, sarcopenia and osteoporosis. Cumulative effects of ageing and HCIAS have been seldom tested and may not always be strictly additive. Data also suggest that some of the metabolic alterations that are more prevalent during ageing could be related more with nutritional habits than to intrinsic ageing. In conclusion, it is clear that HCIAS interacts with the ageing process, accelerates the accumulation of metabolic alterations, and that it should be avoided.

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“…Further investigation on specific and effective GRK2 inhibitors [23] and/or on other strategies [24] able to modulate GRK2 expression or activity in the myocardium and other specific tissues (e.g., adrenal), emerges as an interesting area for future research.…”

Section: Research Highlightmentioning

confidence: 99%

Linking Cardiac Insulin Resistance and Heart Failure: Grk2 as an Integrative Node

Lucas

Jurado-Pueyo

Vila-Bedmar

et al. 2015

Cardiovasc Regen Med

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G protein-coupled receptor kinase 2 (GRK2) has arisen as a signaling hub with critical regulatory roles in cardiac function and dysfunction. Cardiac GRK2 levels are elevated during hypertension, cardiac ischemia and heart failure both in humans and in experimental models, while genetic inhibition of GRK2 results cardioprotective in different animal models of these conditions. However, the mechanistic grounds underlying these effects are not completely understood. Recent research has indicated that GRK2 not only phosphorylates and desensitizes G protein-coupled receptors (GPCR) that are important for heart function such as β-adrenergic or angiotensin type 1, but also modulates other pathways relevant for cardiac physiology such as the insulin signaling cascade. Using GRK2 hemizygous (GRK2+/-) mice, we have unveiled that a lower GRK2 dosage promotes enhanced insulin sensitivity in adult murine hearts what correlates with a cardioprotective gene expression profile. Also, GRK2 levels increase in cardiac tissue in well-established experimental models of systemic insulin resistance, such as high fat diet (HFD) feeding or ob/ob mice what parallels the impaired cardiac insulin sensitivity observed in these conditions. Our findings suggest that pathological inputs of different etiology such as increased catecholamine levels or high dietary fat converge in common important nodes key to the progress of the pathology. One such key connecting hub is GRK2, whose enhanced cardiac expression could promote progression towards maladaptive myocardial remodeling and heart failure.To cite this article: Elisa Lucas, et al. Linking cardiac insulin resistance and heart failure: GRK2 as an integrative node.

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Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats

Cited by 36 publications

References 35 publications

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

The Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

Similarities and interactions between the ageing process and high chronic intake of added sugars

Linking Cardiac Insulin Resistance and Heart Failure: Grk2 as an Integrative Node

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