Cortisol response to stress is associated with myocardial remodeling in salmonid fishes

Abstract

SUMMARYCardiac disease is frequently reported in farmed animals, and stress has been implicated as a factor for myocardial dysfunction in commercial fish rearing. Cortisol is a major stress hormone in teleosts, and this hormone has adverse effects on the myocardium. Strains of rainbow trout (Oncorhynchus mykiss) selected for divergent post-stress cortisol levels [high responsive (HR) and low responsive (LR)] have been established as a comparative model to examine how fish with contrasting stress-coping styles differ in their physiological and behavioral profiles. We show that the mean cardiosomatic index (CSI) of adult HR fish was 34% higher than in LR fish, mainly because of hypertrophy of the compact myocardium. To characterize the hypertrophy as physiological or pathological, we investigated specific cardiac markers at the transcriptional level. HR hearts had higher mRNA levels of cortisol receptors (MR, GR1 and GR2), increased RCAN1 levels [suggesting enhanced pro-hypertrophic nuclear factor of activated T-cell (NFAT) signaling] and increased VEGF gene expression (reflecting increased angiogenesis). Elevated collagen (Col1a2) expression and deposition in HR hearts supported enhanced fibrosis, whereas the heart failure markers ANP and BNP were not upregulated in HR hearts. To confirm our results outside the selection model, we investigated the effect of acute confinement stress in wild-type European brown trout, Salmo trutta. A positive correlation between post-stress cortisol levels and CSI was observed, supporting an association between enhanced cortisol response and myocardial remodeling. In conclusion, post-stress cortisol production correlates with myocardial remodeling, and coincides with several indicators of heart pathology, well-known from mammalian cardiology.

Bigger is not better: cortisol-induced cardiac growth and dysfunction in salmonids

“…The current findings are in line with our previous finding that endogenous stress-induced cortisol production correlates with heart size and remodelling in rainbow trout (Johansen et al, 2011). Our previous investigations were performed on 40 month old (sexually mature) adults that had spent their entire lives under rearing conditions.…”

“…RCAN1 (Rothermel et al, 2001). In the current study, cortisol treatment induced an increase in RCAN1 mRNA expression, which is in line with previous findings of increased RCAN1 expression in rainbow trout with endogenously high plasma cortisol levels (Johansen et al, 2011). Combined, these data indicate prohypertrophic NFAT signalling in the rainbow trout heart in response to chronic elevation of cortisol, and that NFAT signalling in pathological cardiac hypertrophy is conserved from fish to mammals.…”

“…Firststrand cDNA was synthesized from total RNA treated with 2 ng DNase I (DNA-free TM Kit, Ambion) using Superscript III reverse transcriptase (Invitrogen) with oligo dT 12-18 primers synthesized by Invitrogen. Gene-specific primer sequences for rainbow trout β-actin, proliferating cell nuclear antigen (PCNA), ventricular myosin heavy chain (VMHC), slow myosin light chain 2 (SMLC2), muscle LIM protein (MLP), regulator of calcineurin 1 (RCAN1), A-type natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) were designed and published previously (Johansen et al, 2011). The housekeeping gene β-actin was used as a reference gene.…”

“…As in humans, the main glucocorticoid and stress hormone in salmonid fish is cortisol. We previously established a link between cortisol responsiveness to stress and cardiac remodelling in rainbow trout (Oncorhynchus mykiss) high responsive (HR) and low responsive (LR) strains and wild-type brown trout (Salmo trutta) (Johansen et al, 2011). High post-stress cortisol production is also associated with a range of behavioural and cognitive traits indicating a reactive coping style (Øverli et al, 2005Sørensen et al, 2013), rendering the salmonids a productive model to study proximate physiological mechanisms underlying consistent trait associations (Khan et al, 2016).…”

Embryo exposure to elevated cortisol level leads to cardiac performance dysfunction in zebrafish

“…BMPs are key morphogens regulating the expression of genes involved in organogenesis, including heart development Chen et al, 1997), providing a potential link between GR-mediated cortisol signaling and cardiac morphogenesis. There have been studies linking cortisol to abnormal heart development and cardiac gene expression in fetal sheep (Lumbers et al, 2004;Reini et al, 2008) and to cardiac hypertrophy in adult salmon (Johansen et al, 2011). However, few studies have examined the role of cortisol in the developmental regulation of cardiac function in fish.…”