Marinobufagenin as a therapeutic target

National Institute On Aging

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Abstract

To test the above hypothesis, we have performed the following experiment: We studied the effect of a HS diet on blood pressure (BP), CAS, level of steroidal inhibitor of Na/K-ATPase marinobufagenin (MBG) and behavioral function in young DSS rats and normotensive Sprague-Dawley rats (SD), a genetic background and parental breed for DSS rats. We used 8-week-old male SD and DSS rats, which were given a HS diet (8% NaCl; n = 18/group) or low-salt diet (LS; 0.1% NaCl; n = 1418/group) for 8 weeks. The following groups of rats were studied: SD-LS, SD-HS, DSS-LS and DSS-HS. Systolic BP (SBP), the aortic pulse wave velocity (aPWV), a marker of CAS, urine, plasma and brain MBG levels, behavioral test to assess spatial memory (Morris water maze task), plasma and the tissue collection for the histochemical and gene analyses were performed after 8 weeks of a dietary intervention at the end of the experiment. We have found, that 4 months old DSS-LS rats had higher SBP and aPWV and poorer spatial memory than SD-LS rats. The administration of a HS diet increased aPWV, SBP, aortic tissue weight and aortic wall collagen abundance in both strains vs. their LS controls. In SD, HS diet consumption did not affect heart parameters, assessed by echocardiography, vs. SD-LS control, whereas in DSS-HS rats, impaired whole-heart structure and function were observed after HS diet administration vs. DSS-LS rats. The HS diet led to an increase in endogenous plasma, urine and brain MBG levels in both SD and DSS groups. Thus, the prohypertensive and profibrotic effect of HS might be partially attributed to an increase in MBG, because the prohypertensive and profibrotic functions of MBG were pronounced in both DSS and SD rats, although quantitative PCR analysis revealed different profiles of profibrotic genes in DSS and SD rats that was activated after HS intake. Specifically, in SD-HS rats vs. SD-LS, HS intake was associated with an upregulation of LV pro-fibrotic TGF-beta1 (1.5-fold) and CTGF (3-fold) mRNAs, whereas in DSS-HS vs. DSS-LS rats the following profibrotic mRNAs were upregulated: TGF-beta1 (1.5-fold), CTGF (4-fold), FN1 (2.6-fold), Col1alpha2 (2.8-fold) and several other collagen mRNAs, related to fibrosis. Moreover, amyloid precursor protein (APP) gene, related to Alzheimers disease, was activated in DSS-HS only vs. DSS-LS. Interestingly, that spatial hippocampal memory was not affected by HS diet intake in either SD or DSS rats. Based on the results of this experiment, we concluded that: (1) even without HS intake, DSS rats have an early vascular aging which is characterized by CAS and higher blood pressure vs. reasonable control, which was represented by the parental normotensive age-matched SD rats; (2) the impaired cognitive function was associated with higher BP, CAS and cardiovascular remodeling in young 4 months old DSS-LS vs. age-matched SD-LS rats; (3) HS intake had similar effects on SBP, aPWV and urine MBG in DSS and SD rats, although the magnitude of changes of these parameters were higher in DSS than in SD rats; (4) The absence of a cumulative effect of the increased aPWV and BP on spatial memory can be explained by the cerebrovascular and brain plasticity in young 4 months old rats, which help the animals to tolerate CAS and BP, elevated under the condition of a HS intake, and to counterbalance the profibrotic effect of heightened MBG.