Improved heart function follows enhanced inflammatory cell recruitment and angiogenesis in 11βHSD1-deficient mice post-MI

McSweeney, Sara J.; Hadoke, Patrick W. F.; Kozak, Agnieszka M.; Small, Gary; Khaled, Hiba; Walker, Brian R.; Gray, Gillian A.

doi:10.1093/cvr/cvq149

Cited by 59 publications

(93 citation statements)

References 56 publications

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“…However, the peritonitis was actually found to resolve at the same rate as the wildtype animals (44). Similarly, cardiac function was much better preserved in 11β-HSD1 knockout mice following myocardial infarction, despite initially having comparatively higher levels of local inflammation (45,46). Although these studies imply that loss of 11β-HSD1 may not have an adverse impact on an acute inflammatory response, a study using a mouse model of arthritis and carrageenaninduced pleurisy found 11β-HSD1-deficiency to result in the converse (47).…”

Section: European Journal Of Endocrinologymentioning

confidence: 86%

MECHANISMS IN ENDOCRINOLOGY: Tissue-specific activation of cortisol in Cushing’s syndrome

Morgan

Hassan‐Smith

Lavery

2016

European Journal of Endocrinology

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Glucocorticoids are widely prescribed for their anti-inflammatory properties, but have 'Cushingoid' side effects including visceral obesity, muscle myopathy, hypertension, insulin resistance, type 2 diabetes mellitus, osteoporosis, and hepatic steatosis. These features are replicated in patients with much rarer endogenous glucocorticoid (GC) excess (Cushing's syndrome), which has devastating consequences if left untreated. Current medical therapeutic options that reverse the tissue-specific consequences of hypercortisolism are limited. In this article, we review the current evidence that local GC metabolism via the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) plays a central role in mediating the adverse metabolic complications associated with circulatory GC excess -challenging our current view that simple delivery of active GCs from the circulation represents the most important mode of GC action. Furthermore, we explore the potential for targeting this enzyme as a novel therapeutic strategy for the treatment of both endogenous and exogenous Cushing's syndrome.

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Section: European Journal Of Endocrinologymentioning

confidence: 86%

MECHANISMS IN ENDOCRINOLOGY: Tissue-specific activation of cortisol in Cushing’s syndrome

Morgan

Hassan‐Smith

Lavery

2016

European Journal of Endocrinology

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“…Increased recruitment of neutrophils and macrophages within the first days after MI has recently been shown to lead to enhanced neovascularization, a reduction in infarct thinning, and functional improvement in 11␤HSD1-deficient mice. 46 The improved collagen structural organization in the infarct scar in MR MLCCre mice may also be of particular importance, most likely secondary to MMP downregulation. 21 Disorganized collagen matrix renders the scar less resistant to distention during overload and predisposes to thinning and dilatation of the infarcted wall, paving the way for progressive global ventricular dilation, LV dysfunction, and heart failure.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction

et al. 2011

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Background-Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR MLCCre ) that were generated with a conditional MR allele (MR flox ) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter. ) and MR MLCCre mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR MLCCre mice. Chronically infarcted MR MLCCre mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O 2 ⅐Ϫ production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR MLCCre mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-B and reduced apoptosis early after myocardial infarction. Conclusion-Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression. (Circulation. 2011;123:400-408.) Methods and Results-ControlKey Words: acute myocardial infarction Ⅲ aldosterone Ⅲ heart failure Ⅲ mineralocorticoid receptor Ⅲ remodeling M ineralocorticoid receptor (MR) blockade reduces morbidity and mortality in patients with heart failure. 1-4 However, it remains unclear whether the cardioprotective effects of MR antagonists can be attributed to inhibition of the cardiomyocyte MR. While attenuation of left ventricular (LV) dilation and excessive extracellular matrix turnover 5-9 and prevention of electric remodeling appear to be essential mechanisms of MR antagonism, 10,11 extracardiac effects such as renal sodium excretion and potassium sparing, restoration of autonomic balance, and improvement in vascular endothelial dysfunction may be of particular importance. 9,[12][13][14] Clinical Perspective on p 408To investigate the pathophysiological role of the cardiomyocyte MR in ischemic heart failure, we investigated cardiac remodeling after myocardial infarction (MI) in mice with cardiac myocyte-specific inactivation of the MR gene. LV rem...

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“…As a recently published phase II trial shows, these cognitive benefits may not extend into groups with more advanced dementia caused by Alzheimer's disease [91], but should now be tested using drugs targeted to access 11βHSD1 in the central nervous system and in patients with mild cognitive impairment and/or vascular dementia. 11βHSD1 deficiency is also associated with enhanced angiogenesis in ischaemic tissues, resulting, for example, in improved left ventricular function following myocardial infarction in mice and potentially improving wound healing [97,98], a common problem in diabetes. Increased 11βHSD1 activity in ageing human fibroblasts leads to skin ageing and impaired wound healing, and topical application of an 11βHSD1 inhibitor improves wound healing in humans [99,100].…”

Section: Outstanding Challengesmentioning

confidence: 99%

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

et al. 2014

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Cushing's syndrome, caused by increased production of cortisol, leads to metabolic dysfunction including visceral adiposity, hypertension, hyperlipidaemia and type 2 diabetes. The similarities with the metabolic syndrome are striking and major efforts have been made to find obesityassociated changes in the regulation of glucocorticoid action and synthesis, both at a systemic level and tissue level. Obesity is associated with tissue-specific alterations in glucocorticoid metabolism, with increased activity of the glucocorticoidregenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in subcutaneous adipose tissue and decreased conversion of cortisone to cortisol, interpreted as decreased 11βHSD1 activity, in the liver. In addition, genetic manipulation of 11βHSD1 activity in rodents can either induce (by overexpression of Hsd11b1, the gene encoding 11βHSD1) or prevent (by knocking out Hsd11b1) obesity and metabolic dysfunction. Taken together with earlier evidence that non-selective inhibitors of 11βHSD1 enhance insulin sensitivity, these results led to the hypothesis that inhibition of 11βHSD1 might be a promising target for treatment of the metabolic syndrome. Several selective 11βHSD1 inhibitors have now been developed and shown to improve metabolic dysfunction in patients with type 2 diabetes, but the small magnitude of the glucose-lowering effect has precluded their further commercial development.This review focuses on the role of 11βHSD1 as a tissuespecific regulator of cortisol exposure in obesity and type 2 diabetes in humans. We consider the potential of inhibition of 11βHSD1 as a therapeutic strategy that might address multiple complications in patients with type 2 diabetes, and provide our thoughts on future directions in this field.

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Improved heart function follows enhanced inflammatory cell recruitment and angiogenesis in 11βHSD1-deficient mice post-MI

Cited by 59 publications

References 56 publications

MECHANISMS IN ENDOCRINOLOGY: Tissue-specific activation of cortisol in Cushing’s syndrome

MECHANISMS IN ENDOCRINOLOGY: Tissue-specific activation of cortisol in Cushing’s syndrome

Deletion of Cardiomyocyte Mineralocorticoid Receptor Ameliorates Adverse Remodeling After Myocardial Infarction

Tissue-specific dysregulation of cortisol regeneration by 11βHSD1 in obesity: has it promised too much?

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