Background: Cardiac hypertrophy increases the risk of developing heart failure and cardiovascular death. The neutrophil inflammatory protein, lipocalin‐2 ( LCN 2/ NGAL ), is elevated in certain forms of cardiac hypertrophy and acute heart failure. However, a specific role for LCN 2 in predisposition and etiology of hypertrophy and the relevant genetic determinants are unclear. Here, we defined the role of LCN 2 in concentric cardiac hypertrophy in terms of pathophysiology, inflammatory expression networks, and genomic determinants. Methods and Results: We used 3 experimental models: a polygenic model of cardiac hypertrophy and heart failure, a model of intrauterine growth restriction and Lcn2 ‐knockout mouse; cultured cardiomyocytes; and 2 human cohorts: 114 type 2 diabetes mellitus patients and 2064 healthy subjects of the YFS (Young Finns Study). In hypertrophic heart rats, cardiac and circulating Lcn2 was significantly overexpressed before, during, and after development of cardiac hypertrophy and heart failure. Lcn2 expression was increased in hypertrophic hearts in a model of intrauterine growth restriction, whereas Lcn2 ‐knockout mice had smaller hearts. In cultured cardiomyocytes, Lcn2 activated molecular hypertrophic pathways and increased cell size, but reduced proliferation and cell numbers. Increased LCN 2 was associated with cardiac hypertrophy and diastolic dysfunction in diabetes mellitus. In the YFS , LCN 2 expression was associated with body mass index and cardiac mass and with levels of inflammatory markers. The single‐nucleotide polymorphism, rs13297295, located near LCN 2 defined a significant cis ‐ eQTL for LCN 2 expression. Conclusions: Direct effects of LCN 2 on cardiomyocyte size and number and the consistent associations in experimental and human analyses reveal a central role for LCN 2 in the ontogeny of cardiac hypertrophy and heart failure.

Leukocyte telomeres shorten with age, and excessive shortening is associated with age-related cardiometabolic diseases. Exercise training may prevent disease through telomere length maintenance although the optimal amount of exercise that attenuates telomere attrition is unknown. Furthermore, the underlying molecular mechanisms responsible for the enhanced telomere maintenance observed in endurance athletes is poorly understood. We quantified the leukocyte telomere length and analyzed the expression of telomere-regulating genes in endurance athletes and healthy controls (both n = 61), using quantitative PCR. We found endurance athletes have significantly longer (7.1%, 208-416 nt) leukocyte telomeres and upregulated TERT (2.0-fold) and TPP1 (1.3-fold) mRNA expression compared with controls in age-adjusted analysis. The telomere length and telomere-regulating gene expression differences were no longer statistically significant after adjustment for resting heart rate and relative V̇o_{2 max} (all P > 0.05). Resting heart rate emerged as an independent predictor of leukocyte telomere length and TERT and TPP1 mRNA expression in stepwise regression models. To gauge whether volume of exercise was associated with leukocyte telomere length, we divided subjects into running and cycling tertiles (distance covered per week) and found individuals in the middle and highest tertiles had longer telomeres than individuals in the lowest tertile. These data emphasize the importance of cardiorespiratory fitness and exercise training in the prevention of biological aging. They also support the concept that moderate amounts of exercise training protects against biological aging, while higher amounts may not elicit additional benefits.

MicroRNAs (miRNA) are small non-coding RNA molecules that regulate gene expression post-transcriptionally. Evidence indicating miRNAs influence exercise-induced health and performance adaptations is mounting. Circulating microRNAs are responsible for intercellular communication and could serve as biomarkers for disease and exercise-related traits. Such biomarkers would contribute to exercise screening, monitoring and the development of personalised exercise prescription. Accordingly, we investigated the impact of long-term strenuous aerobic exercise training and a single bout of maximal aerobic exercise on five muscle-enriched miRNAs implicated in exercise adaptations (miR-1, miR-133a, miR-181a, miR-486 and miR-494). We also determined linear correlations between miRNAs, resting heart rate and maximal oxygen uptake (V ̇O2max). We used TaqMan assay quantitative PCR to analyse the abundance of miR-1, miR-133a, miR-181a, miR-486 and miR-494 in resting whole blood of 67 endurance athletes and 61 healthy controls. Relative to controls, endurance athletes exhibited increased miR-1, miR-486 and miR-494 content (1.26–1.58-fold change, all p<0.05). miR-1, miR-133a and miR-486 were decreased immediately after maximal aerobic exercise (0.64–0.76-fold change, all p<0.01) performed by 19 healthy, young men (20.7±2.4 y). Finally, we observed positive correlations between miRNA abundance and V ̇O2max (miR-1 and miR-486) and an inverse correlation between miR-486 and resting heart rate. Therefore, muscle-enriched miRNAs isolated from whole blood are regulated by acute and long-term aerobic exercise training and could serve as biomarkers of cardiorespiratory fitness.

Genome-wide association studies (GWAS) have identified >100 loci of chronic kidney disease-defining traits (CKD-dt). Molecular mechanisms underlying these associations remain elusive. Using 280 kidney transcriptomes and 9958 gene expression profiles from 44 non-renal tissues we uncover gene expression partners (eGenes) for 88.9% of CKD-dt GWAS loci. Through epigenomic chromatin segmentation analysis and variant effect prediction we annotate functional consequences to 74% of these loci. Our colocalisation analysis and Mendelian randomisation in >130,000 subjects demonstrate causal effects of three eGenes (NAT8B, CASP9 and MUC1) on estimated glomerular filtration rate. We identify a common alternative splice variant in MUC1 (a gene responsible for rare Mendelian form of kidney disease) and observe increased renal expression of a specific MUC1 mRNA isoform as a plausible molecular mechanism of the GWAS association signal. These data highlight the variants and genes underpinning the associations uncovered in GWAS of CKD-dt.

Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype-Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.