Salt loading exacerbates diastolic dysfunction and cardiac remodeling in young female Ren2 rats.
OBJECTIVE
Recent data would suggest pre-menopausal insulin resistant women are more prone to diastolic dysfunction than men, yet it is unclear why. We and others have reported that transgenic (mRen2)27 (Ren2) rats overexpressing the murine renin transgene are insulin resistant due to oxidative stress in insulin sensitive tissues. As increased salt intake promotes inflammation and oxidative stress, we hypothesized that excess dietary salt would promote diastolic dysfunction in transgenic females under conditions of excess tissue Ang II and circulating aldosterone levels.


METHODS
For this purpose we evaluated cardiac function in young female Ren2 rats or age-matched Sprague-Dawley (SD) littermates exposed to a high (4%) salt or normal rat chow intake for three weeks.


RESULTS
Compared to SD littermates, at 10weeks of age, female Ren2 rats fed normal chow showed elevations in left ventricular (LV) systolic pressures, LV and cardiomyocyte hypertrophy, and displayed reductions in LV initial filling rate accompanied by increases in 3-nitrotyrosine content as a marker of oxidant stress. Following 3weeks of a salt diet, female Ren2 rats exhibited no further changes in LV systolic pressure, insulin resistance, or markers of hypertrophy but exaggerated increases in type 1 collagen, 3-nitrotryosine content, and diastolic dysfunction. These findings occurred in parallel with ultrastructural findings of pericapillary fibrosis, increased LV remodeling, and mitochondrial biogenesis.


CONCLUSIONS
These data suggest that a diet high in salt in hypertensive female Ren2 rats promotes greater oxidative stress, maladaptive LV remodeling, fibrosis, and associated diastolic dysfunction without further changes in LV systolic pressure or hypertrophy.
Research Service Harry S Truman Memorial Veterans Hospital, Research Service, 800 Hospital Dr, Columbia, MO 65212, USA; University of Missouri School of Medicine, Departments of Internal Medicine, Divisions of Nephrology and Hypertension, Columbia, MO, USA; University of Missouri School of Medicine, Departments of Internal Medicine, Division of Endocrinology and Metabolism, Columbia, MO, USA; University of Missouri School of Medicine, Diabetes and Cardiovascular Center, Columbia, MO, USA. Electronic address: adam.whaley-connell@va.gov.
Adam T
AT
Whaley-Connell
Javad
J
Habibi
Annayya
A
Aroor
Lixin
L
Ma
Melvin R
MR
Hayden
Carlos M
CM
Ferrario
Vincent G
VG
Demarco
James R
JR
Sowers
D000818:Animals; D003094:Collagen / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000473:pathology; D005455:Fluorescent Antibody Technique; D054144:Heart Failure, Diastolic / Q000139:chemically induced* / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000473:pathology; D008279:Magnetic Resonance Imaging; D046529:Microscopy, Electron, Transmission; D008929:Mitochondria, Heart / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D012982:Sodium, Dietary / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D016277:Ventricular Function, Left / Q000502:physiology
D012982:Sodium, Dietary; C002744:3-nitrotyrosine; D014443:Tyrosine; D003094:Collagen
3-NT; 3-nitrotyrosine; Ang II; Angiotensin II; BW; Cox IV; DRT; HR; IFR; LV; LVH; LVV; MR; MRI; Oxidative stress; Perivascular fibrosis; QUICKI; RAAS; Ren2; Ren2 4% salt; Ren2-HS; S; SBP; SD; Sprague–Dawley; TEM; TG (mRen2) 27 rat; angiotensin II; body weight; cytochrome oxidase IV; diastolic relaxation time; heart rate; initial filing rate; left ventricular; left ventricular hypertrophy; left ventricular volume; magnetic resonance imaging; mineralocorticoid receptor; quantitative insulin sensitivity check index; renin-angiotensin-aldosterone system; septal; systolic blood pressure; transgenic (mRen2)27; transmission electron microscopy