Salt Excess Causes Left Ventricular Diastolic Dysfunction in Rats With Metabolic Disorder

Abstract

Abstract-Metabolic syndrome is a highly predisposing condition for cardiovascular disease and could be a cause of excess salt-induced organ damage. Recently, several investigators have demonstrated that salt loading causes left ventricular diastolic dysfunction associated with increased oxidative stress and mineralocorticoid receptor activation. We, therefore, investigated whether excess salt induces cardiac diastolic dysfunction in metabolic syndrome via increased oxidative stress and upregulation of mineralocorticoid receptor signals. Thirteen-week-old spontaneously hypertensive rats and SHR/NDmcr-cps, the genetic model of metabolic syndrome, were fed a normal salt (0.5% NaCl) or high-salt (8% NaCl) diet for 4 weeks. In SHR/NDmcr-cps, salt loading induced severe hypertension, abnormal left ventricular relaxation, and perivascular fibrosis. Salt-loaded SHR/NDmcr-cps also exhibited overproduction of reactive oxygen species and upregulation of mineralocorticoid receptor-dependent gene expression, such as Na ϩ /H ϩ exchanger-1 and serumand glucocorticoid-inducible kinase-1 in the cardiac tissue. However, in spontaneously hypertensive rats, salt loading did not cause these cardiac abnormalities despite a similar increase in blood pressure. An antioxidant, tempol, prevented salt-induced diastolic dysfunction, perivascular fibrosis, and upregulation of mineralocorticoid receptor signals in SHR/NDmcr-cps. Moreover, a selective mineralocorticoid receptor antagonist, eplerenone, prevented not only diastolic dysfunction but also overproduction of reactive oxygen species in salt-loaded SHR/NDmcr-cps. These results suggest that metabolic syndrome is a predisposed condition for salt-induced left ventricular diastolic dysfunction, possibly via increased oxidative stress and enhanced mineralocorticoid receptor signals. which eventually leads to diastolic heart failure with a poor prognosis. 5,6 However, LV diastolic dysfunction has not always been seen in a MetS animal model. For example, in obesity-prone Sprague-Dawley rats, a moderate fat diet induced metabolic abnormalities but did not cause LV diastolic dysfunction. 7 This discrepancy indicates a possibility that some exogenous factors deteriorate cardiac function in MetS. In patients with MetS, high salt intake increased blood pressure (BP) greater than in those without MetS. 8 In an MetS rat model, evident renal injury was induced by salt loading. 9 These findings suggest that the MetS model is highly susceptible to salt-induced organ damage. Salt loading induced LV hypertrophy or LV diastolic dysfunction in several hypertension models. 10 -14 Therefore, it is speculated that LV diastolic impairment could be accelerated with excess salt in an MetS model.Reactive oxygen species (ROS) are important elements causing cardiac functional damage. 10,15,16 MetS should be associated with an increase in oxidative stress, 17-19 possibly through enhanced ROS-inducible adipocytokines. 20 -22 Also, salt loading increased oxidative stress in several salt-sensitive hypertension models...

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

“…A transient increase in p38 phosphorylation was observed during the pre-ischemic period, while attenuation of its phosphorylation was observed during ischemia-reperfusion; these effects may be deeply involved in the cardioprotective effects of aldosterone preconditioning. It has been well documented that the persistent excessive actions of aldosterone, commonly by a combination of salt loading, cause adverse cardiovascular effects primarily via MR-dependent pathways (Matsui et al 2008. On the other hand, ourselves and others have recently reported that aldosterone exerts transient but favorable effects on cardiocytes in vitro, mainly via rapid MR-independent actions (Yamamuro et al 2006, Bunda et al 2009, Nagoshi et al 2012.…”

“…There is increasing evidence of unfavorable effects of aldosterone on the cardiovascular system, in experimental models as well as large clinical trials (Pitt et al 2003), primarily via mineralocorticoid receptor (MR)-dependent actions (Caprio et al 2008, Matsui et al 2008, Rickard et al 2012, Sherajee et al 2012, Diaz et al 2014, Nolly et al 2014). …”

Cardiac remodeling and diastolic dysfunction in DahlS.Z-Leprfa/Leprfa rats: a new animal model of metabolic syndrome

“…18 DS/obese rats developed hypertension and showed impairment of LV relaxation as well as an increase in the extents of LV perivascular and interstitial fibrosis, and these changes were accompanied by upregulation of TGF-b1 and CTGF mRNAs in the heart, consistent with previous observations showing that these growth factors are involved in the development of LV remodeling in a rat model of heart failure 28 and in SHR/NDmcr-cp rats fed a high-salt diet. 8 Macrophages have been implicated in fibrosis associated with various pathological conditions. In the present study, macrophage infiltration into the interstitial space of the myocardium was accompanied by upregulation of the expression of genes for proinflammatory chemokines and cytokines, including those for monocyte chemoattractant protein-1, TNF-a and IL-6, in the heart of DS/obese rats.…”

“…34 We found that both NADPHdependent superoxide generation and the expression of NADPH oxidase subunit genes were increased in the heart of DS/obese rats, consistent with data from SHR/NDmcr-cp rats. 8 Excess reactive oxygen species may contribute to impairment of LV diastolic function through inhibition of Ca 2+ -handling proteins. 35 In addition to impairments in metabolic signaling and oxidative stress, genetic and environmental factors, aging and hyperglycemia all contribute to reduced mitochondrial biogenesis and mitochondrial dysfunction.…”

“…7 On the other hand, the SHR (spontaneously hypertensive rat)/ NDmcr-cp rat, a genetic model of MetS that is a derivative of the SHR with deficiency of the leptin receptor, was shown to develop severe hypertension and LV diastolic dysfunction as well as LV hypertrophy and coronary perivascular fibrosis when fed a high-salt diet. 8 We recently established a new animal model of MetS, the DahlS.Z-Lepr fa / Lepr fa (Dahl salt-sensitive (DS)/obese) rat, by crossing DS rats and Zucker rats with a missense mutation in the leptin receptor gene (Lepr). Male DS/obese rats develop a phenotype similar to MetS in humans, including hypertension, when fed a normal diet.…”