Predominant Alterations in the Gene Expression Pattern of Molecules Involved in Immune Reaction and Cell Stress in the Aging Myocardium

Objectives: Aging myocardium on normal and especially on diabetic conditions is characterized by numerous changes which finally lead to lower left ventricular ejection fraction and, therefore, circulatory dysfunction. Besides known age-associated changes, such as collagen depositions and differences in the intracellular calcium gradient, many changes might still be unknown.

Methods: Therefore, we analyzed left ventricular myocardium of adult (6 months) and old (24 months) mice as well as of old mice having been treaded life-long with methylglyoxal (MG), a diabetes-related metabolite, for their gene expression pattern by use of Affymetrix GeneChip Mouse Genome 430 2.0 arrays.

Results: Absolute and body weight-normalized heart weight was higher in old than in adult mice but not influenced by MG treatment. 24-month-survial was also not influenced by MG. After application of defined exclusion criteria, ~150 genes were identified to be differentially expressed in old hearts. Among them were marker genes indicating myocardial overload/dysfunction (natriuretic peptide type A and its activator corin, cardiac ryanodine receptor 2) and cellular senescence (cyclin-dependent kinase inhibitor 1A). Nearly one third of the age-regulated genes identified codes for proteins indicating more immune reactions in older hearts, such as chemokines (CCLs −6, −8, −9, −12), S100 proteins (S100s 6, 9, 10, 16), complement factors and markers of lymphatic vessels. Moreover, we identified genes coding for proteins directly involved in myocardial cell death by endoplasmic reticulum (ER) stress (caspases −4, −12) as well as genes of which their myocardial importance has been discovered just recently (ankyrin repeat domain 1, follistatin-like 1, PTEN-induced putative kinase 1, renalase) or is not yet discovered (biglycan, phosphatidylserine decarboxylase). Many genes differentially expressed in old hearts were not additionally regulated by the life-long MG treatment. In some cases, we detected an exclusive effect of the MG treatment (ADP-ribosylhydrolase like 1, caspase-8, heme oxygenase 1).

Conclusion: Myocardial aging is associated with an altered expression pattern of molecules involved in immune reaction and ER stress but also less known molecules of which the age-related importance has still to be found out. Regarding hypertrophy and expression pattern, the diabetes-related metabolite MG had less importance on myocardial aging than expected.