Sex-dependent deterioration of cardiac function and molecular alterations in age- and disease-associated RAGE overexpression. (April 2022)

• Record Type: Journal Article
• Authors: Winterhalter, Patrick R.; Wirkner, Mandy; Bartling, Babett; Wächter, Kristin; Urazova, Arina; Großkopf, Anne; Diez, Claudius; Szabó, Gábor; Simm, Andreas
• Is Part Of: Mechanisms of ageing and development. Volume 203(2022)
• Publication Date: 2022-04
• Subjects: Receptor for advanced-glycation endproducts (RAGE) -- Geriatric -- Ageing -- Left ventricular ejection fraction (EF) reduction -- Cardiac ATP depletion -- Ferritin heavy chain 1 (FRIH -- FTH1) -- Four-and-a-half LIM-domains protein 2 (FHL2) -- Aging -- Gender -- Sex differences; Aging -- Periodicals; Developmental biology -- Periodicals; Aging -- Periodicals; Developmental Biology -- Periodicals; Vieillissement -- Périodiques; Biologie du développement -- Périodiques; Aging; Developmental biology; Periodicals; 612.67
• DOI: 10.1016/j.mad.2022.111635
• Languages: English
• ISSNs: 0047-6374

Abstract

Abstract: Elevated expression of the receptor for advanced-glycation endproducts (RAGE) in cardiac tissue is well-known in the elderly, in diabetes mellitus, and after acute cardiac infarction or ischemia/reperfusion injuries. RAGE and its binding partners affect the clinical outcome of heart failure and may play an essential role in accelerating the functional decline in cardiovascular aging. Therefore, hearts of wild-type (WT) C57black6/N and cardiac-specific RAGE-overexpressing transgenic (TR) mice were analyzed for their function by ultrasound at young (4–5 months) and old (22–23 months) ages. Transgenic mice exhibit significantly increased systolic (LVD-sy) and diastolic (LVD-di) diameters of their left ventricles. The left ventricular ejection fraction (EF) was significantly reduced in young male TR mice. Omics of the heart did not reveal direct activation of cytokine-induced inflammation. Instead, energy metabolism-associated genes were enriched in downregulated transcripts and proteins of TR animals, causing decreased ATP production. In a sex-specific manner, there was a reduced expression of the four-and-a-half LIM-domains protein 2 (FHL2). In conclusion, transgene-induced RAGE overexpression, as a model for age- and disease-associated RAGE alteration, leads to a sex-dependent EF decline, in which FHL2 and energy depletion might play crucial roles. Highlights: Cardiac overexpression of RAGE in mice reduces the left ventricular ejection fraction prevalently male-specific. RAGE overexpression did not result in chronic cytokine-associated inflammation. Omics data reveal an altered energy metabolism, consistent with diminished ATP production in RAGE-overexpressing animals. Overexpression of RAGE is associated with a decrease in the proteins of FRIH (general) and FHL2 (male-specific).