title: Cardiomyocyte mineralocorticoid receptors are essential for deoxycorticosterone/salt-mediated inflammation and cardiac fibrosis.
abstract: Because the role of mineralocorticoid receptors in specific cell types in cardiac remodeling remains unknown, we have compared cardiac responses with deoxycorticosterone/salt in cardiomyocyte mineralocorticoid receptor-null (MyoMRKO) and wild-type (WT) mice at 8 days and 8 weeks. No differences in cardiac function between untreated WT and MyoMRKO mice were found, whereas profibrotic markers were reduced in MyoMRKO hearts at baseline. At 8 days, MyoMRKO showed monocyte/macrophage recruitment equivalent to WT mice in response to deoxycorticosterone/salt but a suppression of markers of fibrosis compared with WT. At 8 weeks, MyoMRKO mice showed no deoxycorticosterone/salt-induced increase in inflammatory cell infiltration and collagen deposition or in proinflammatory gene expression. Although some profibrotic markers were equivalently increased in both genotypes, MyoMRKO mice also showed increased baseline levels of mRNA and protein for the transforming growth factor-β/connective tissue growth factor inhibitor decorin compared with WT that was accompanied by higher levels of matrix metalloproteinase 2/matrix metalloproteinase 9 activity. These data point to a direct role for cardiomyocyte mineralocorticoid receptor in both deoxycorticosterone/salt-induced tissue inflammation and remodeling and suggest potential mechanisms for the cardioprotective effects of selective mineralocorticoid receptor blockade in cardiomyocytes that may involve regulation of matrix metalloproteinase 2/matrix metalloproteinase 9 activity and the transforming growth factor-β-connective tissue growth factor profibrotic pathway.
authors.affiliation: Prince Henry’s Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Rickard
authors.forename: James
authors.initials: J
authors.lastname: Morgan
authors.forename: Laura A
authors.initials: LA
authors.lastname: Bienvenu
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Fletcher
authors.forename: Greg A
authors.initials: GA
authors.lastname: Cranston
authors.forename: Jimmy Z
authors.initials: JZ
authors.lastname: Shen
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Reichelt
authors.forename: Lea M
authors.initials: LM
authors.lastname: Delbridge
authors.forename: Morag J
authors.initials: MJ
authors.lastname: Young
mesh_terms: D000818:Animals; D003900:Desoxycorticosterone / Q000494:pharmacology*; D005355:Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism*; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D018161:Receptors, Mineralocorticoid; D017673:Sodium Chloride, Dietary; D003900:Desoxycorticosterone; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9