Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

Fukui, Shigefumi; Fukumoto, Yoshihiro; Suzuki, Jun; K, Saji; Nawata, Jun; Shinozaki, Tsuyoshi; Kagaya, Yutaka; Watanabe, Jun; Shimokawa, Hiroaki

doi:10.1038/hr.2009.43

Cited by 26 publications

(23 citation statements)

References 53 publications

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“…40 In combination with hypertension, Fukui et al 41 observed that DM accelerates LV diastolic dysfunction via renin-angiotensin system in hypertensive rats. Taken together, hypertension and DM could synergistically deteriorate diastolic function in human.…”

Section: Renin-angiotensin System and Opn Expressionmentioning

confidence: 99%

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

et al. 2011

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Heart failure with preserved ejection fraction is recently highlighted as a major health problem, and diastolic dysfunction associated with hypertension has a dominant role in the development of heart failure with preserved ejection fraction. Osteopontin (OPN) is a secreted phosphoprotein, which mediates fibrosis. In animal models, OPN is upregulated in response to pressure overload and is thought to be involved in systolic dysfunction. However, the functional role of OPN in diastolic dysfunction is unknown. The guanine base insertion polymorphism at À156 position of the OPN promoter is postulated to upregulate the transcription of OPN in human. To investigate whether À156del/G polymorphism of OPN promoter is associated with diastolic dysfunction in hypertensive hearts, the patients with hypertension have been genotyped for variants of À156del/G polymorphism by genomic sequencing. Diastolic function of the left ventricle was estimated as the ratio of early to atrial filling (E/A ratio), obtained by pulsed-Doppler derived transmitral flow in echocardiographic analysis. The patients with À156G allele displayed lower E/A ratio compared with those with À156del/del genotype, suggesting exacerbated diastolic function. Notably, in case of the population with diabetes mellitus, the patients with À156G allele showed significant association with lower E/A ratio, compared with À156del/À156del patients. Multiple linear regression analysis revealed that prevalence of À156G allele was an independent factor for lowering E/A ratio. The À156del/G genetic variants of OPN promoter were associated with decreased E/A ratio in hypertensive patients. These results suggest that OPN has a functional role in the development of diastolic dysfunction in hypertensive hearts.

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Section: Renin-angiotensin System and Opn Expressionmentioning

confidence: 99%

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

et al. 2011

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“…To determine myocyte cross-sectional area (CSA), 30 cardiomyocytes were traced in each section in the slides stained with HE using NIH Image software. The percentage area of perivascular and interstitial fibrosis in the LV at the papillary muscle level in the slides stained with MT and SR was determined (6,8). The remaining LV was immediately placed in liquid nitrogen and stored at Ϫ80°C for Western blot analyses.…”

Section: Methodsmentioning

confidence: 99%

Repetitive hyperthermia attenuates progression of left ventricular hypertrophy and increases telomerase activity in hypertensive rats

Oyama

Maeda

Sasaki

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Repetitive hyperthermia attenuates progression of left ventricular hypertrophy and increases telomerase activity in hypertensive rats. Am J Physiol Heart Circ Physiol 302: H2092-H2101, 2012. First published March 16, 2012 doi:10.1152/ajpheart.00225.2011.-We investigated the hypothesis that repetitive hyperthermia (RHT) attenuates the progression of cardiac hypertrophy and delays the transition from hypertensive cardiomyopathy to heart failure in Dahl saltsensitive (DS) hypertensive rats. Six-week-old DS rats were divided into the following five groups: a normal-salt diet (0.4% NaCl) (NS group), a normal-salt diet plus RHT by daily immersion for 10 min in 40°C water (NSϩRHT group), a high-salt diet (8% NaCl) (HS group), a high-salt diet (8% NaCl) plus RHT (HSϩRHT group), and high-salt diet (8% NaCl) plus RHT with 17-DMAG (HSP90 inhibitor) administration (HSϩRHTϩ17-DMAG group). All rats were killed at 10 wk. Cardiac hypertrophy and fibrosis were noted in the HS group, whereas RHT attenuated salt-induced cardiac hypertrophy, myocardial and perivascular fibrosis, and blood pressure elevation. The phosphorylated endothelial nitric oxide synthase (eNOS) and Akt were decreased in the HS group compared with the NS group, but these changes were not observed in the HSϩRHT group. The levels of HSP60, 70, and 90 were elevated by RHT. Moreover, the increased levels of iNOS, nitrotyrosine, Toll-like receptor-4, BNP, PTX3, and TBARS in the HS group were inhibited by RHT. Telomeric DNA length, telomerase activity, and telomere reverse transcriptase (TERT) were reduced in the HS group; however, these changes were partially prevented by hyperthermia. In conclusion, RHT attenuates the development of cardiac hypertrophy and fibrosis and preserves telomerase, TERT activity and the length of telomere DNA in salt-induced hypertensive rats through activation of eNOS and induction of HSPs. cardiac hypertrophy; endothelial nitric oxide synthase; oxidative stress; telomere; heat shock protein HYPERTENSION IS ONE OF MAJOR risk factors responsible for cardiovascular disease and may lead to cardiac hypertrophy and diastolic heart failure (DHF). DHF is defined as heart failure with preserved left ventricular (LV) contraction and is characterized by abnormal relaxation and/or increased stiffness of the LV leading to impaired filling during diastole. Typically, diastolic function is evaluated by the E/A ratio using echocardiography. LV diastolic dysfunction is often manifested in individuals with hypertension. About 30 -40% of heart failure cases occur in patients with diastolic dysfunction and normal systolic function (28,36). Cardiac hypertrophy and resultant fibrosis develop as an adaptive response to pressure overload in hypertension and are commonly associated with DHF. Progressive cardiac remodeling characterized by LV hypertrophy, chamber enlargement, and pump dysfunction occurs in response to hypertension and is accompanied by progressive accumulation of the extracellular matrix (36).Hyperthermia using dry sauna improves cardiac functio...

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“…LV ejection fraction and relative wall thickness were calculated as previously described. 22 LV diastolic function was assessed by the measurement of LV transmitral early peak flow velocity (E) to LV transmitral late peak flow velocity (A) wave ratio (E/A ratio). 22 …”

Section: Echocardiographymentioning

confidence: 99%

SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis

et al. 2016

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The detailed molecular mechanisms of the pleiotropic effects of statins remain to be fully elucidated. Here, we hypothesized that cardioprotective effects of statins are mediated by small GTP-binding protein GDP dissociation stimulator (SmgGDS). SmgGDS +/– and wild-type (WT) mice were treated with continuous infusion of angiotensin II (Ang II) for 2 weeks with and without oral treatment with atorvastatin or pravastatin. At 2 weeks, the extents of Ang II–induced cardiac hypertrophy and fibrosis were comparable between the 2 genotypes. However, statins significantly attenuated cardiomyocyte hypertrophy and fibrosis in WT mice, but not in SmgGDS +/– mice. In SmgGDS +/– cardiac fibroblasts (CFs), Rac1 expression, extracellular signal–regulated kinases 1/2 activity, Rho-kinase activity, and inflammatory cytokines secretion in response to Ang II were significantly increased when compared with WT CFs. Atorvastatin significantly reduced Rac1 expression and oxidative stress in WT CFs, but not in SmgGDS +/– CFs. Furthermore, Bio-plex analysis revealed significant upregulations of inflammatory cytokines/chemokines and growth factors in SmgGDS +/– CFs when compared with WT CFs. Importantly, conditioned medium from SmgGDS +/– CFs increased B-type natriuretic peptide expression in rat cardiomyocytes to a greater extent than that from WT CFs. Furthermore, atorvastatin significantly increased SmgGDS secretion from mouse CFs. Finally, treatment with recombinant SmgGDS significantly reduced Rac1 expression in SmgGDS +/– CFs. These results indicate that both intracellular and extracellular SmgGDS play crucial roles in the inhibitory effects of statins on cardiac hypertrophy and fibrosis, partly through inhibition of Rac1, Rho kinase, and extracellular signal–regulated kinase 1/2 pathways, demonstrating the novel mechanism of the pleiotropic effects of statins.

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Diabetes mellitus accelerates left ventricular diastolic dysfunction through activation of the renin–angiotensin system in hypertensive rats

Cited by 26 publications

References 53 publications

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

Repetitive hyperthermia attenuates progression of left ventricular hypertrophy and increases telomerase activity in hypertensive rats

SmgGDS as a Crucial Mediator of the Inhibitory Effects of Statins on Cardiac Hypertrophy and Fibrosis

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