Interleukin-17 aggravates right ventricular remodeling via activating STAT3 under both normoxia and hypoxia

Abstract Objective Proinflammatory cytokine interleukin 17 (IL-17) is involved in ventricular remodeling, mainly of the left ventricle. This study was designed to explore the role of IL-17 played in the pathogenesis of right ventricular hypertrophy (RVH), aiming to provide a novel treatment target or diagnostic biomarker options for improving the care of RVH patients. Methods C57BL/6 mice were maintained in 10% O2 chamber or room air for four weeks. Right ventricular hypertrophy index (RVHI), RV/body weight ratio, pulmonary arteriolar remodeling determined by percent media thickness (%MT), and the cardiomyocyte diameter of RV were evaluated. Mice were treated with exogenous recombinant mouse IL-17 (rmIL-17, 1 μg per dose twice a week) for four weeks. H9c2 cardiomyocytes were cultured and treated with IL-17 (10 ng/mL) and STAT3 inhibitor (10 ng/mL) either under normoxia (21% O2, 5% CO2, 74% N2) or under hypoxia (3% O2, 5% CO2, 92% N2). Cardiomyocyte viability was assessed by Cell counting kit 8 (CCK-8) assay. The mRNA level was detected by RT-PCR, where as the protein expression was measured by Western blot, immunohistochemistry, and immunofluorescent analyses. Results In vivo experiments showed that IL-17 did not affect the pulmonary artery under normoxia, after treatment with rmIL-17, %MT was not changed, while RVHI and the RV/body weight ratio were increased, indicating that IL-17 directly induced right ventricular hypertrophy. In a time-course study, the mice were exposed to hypoxia for 0, 1, 2, 3, 4 weeks, respectively. We found that the expression of IL-17 was gradually upregulated in RV tissue in a time-dependent manner after one week of hypoxia exposure, especially at the third and fourth week. Cardiomyocyte hypertrophy and apoptosis were observed after the exposure of the mice to hypoxia for four weeks, rmIL-17 further aggravated the hypoxia-induced cardiomyocyte hypertrophy and apoptosis. The expression of p-STAT3 in the IL-17-deficient mice was lower than in the wild-type mice. In vitro, IL-17 inhibited cardiomyocyte viability and induced cardiomyocyte apoptosis via STAT3 under both normoxic and hypoxic conditions. Conclusions These findings support a role for IL-17 as a mediator in the pathogenesis RVH, which might be considered as a potential novel anti-inflammation therapeutic strategy or diagnostic biomarker for RVH.

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Abstract 15303: Dimethylarginine Dimethylaminohydrolase-1 is Not Involved in Chronic Hypoxic Pulmonary Hypertension and Right Ventricular Hypertrophy in Mice

Circulation ◽

10.1161/circ.142.suppl_3.15303 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Juliane Hannemann ◽

Antonia Glatzel ◽

Jonas Hillig ◽

Julia Zummack ◽

Rainer H Boeger

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Chronic Hypoxia ◽

Right Ventricular Hypertrophy ◽

Cardiomyocyte Hypertrophy ◽

No Production ◽

Knock Out ◽

Knock Out Mice ◽

Adma Concentration

Introduction: Chronic hypoxia causes persistent pulmonary vasoconstriction and leads to pulmonary hypertension and right ventricular hypertrophy. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis; its level increases in hypoxia concomitantly with reduced activity of dimethylarginine dimethylaminohydrolases (DDAH-1 and DDAH-2), the enzymes metabolizing ADMA. DDAH knockout models may therefore help to understand the pathophysiological roles of this enzyme and its substrate, ADMA, in the development of hypoxia-associated pulmonary hypertension. Hypothesis: We hypothesized that DDAH1 knock-out mice have an attenuated hypoxia-induced elevation of ADMA and reduced right ventricular hypertrophy. Methods: DDAH1 knock-out mice (KO) and their wild-type littermates (WT) were subjected to normoxia (NX) or hypoxia (HX) during 21 days. We measured ADMA concentration in plasma, DDAH1 and DDAH2 expression in the lung, right ventricular hypertrophy by the Fulton index, cardiomyocyte hypertrophy by dystrophin staining of heart tissues, and muscularization of pulmonary arterioles by CD31 and α-actin staining of lung sections. Results: DDAH1 KO mice had higher ADMA concentration than WT under NX (2.31±0.33 μmol/l vs. 1.20±0.17 μmol/l; p < 0.05). ADMA significantly increased in WT-HX (to 1.74±0.86 μmol/l; p < 0.05 vs. normoxia), whilst it did not further increase in KO-HX (2.58±0.58 μmol/l; p = n.s.). This was paralleled by a 38±13% reduction in DDAH1 mRNA but not DDAH2 mRNA expression, and reduced DDAH protein expression. We observed right ventricular hypertrophy under hypoxia in both, WT and KO mice, with no significant differences between both genotypes. Further, cardiomyocyte hypertrophy and pulmonary arteriolar muscularization were significantly increased by hypoxia, but not significantly different between WT and KO mice. Conclusions: We conclude that chronic hypoxia causes an elevation of ADMA, which impairs NO production and leads to endothelial dysfunction and vasoconstriction. Downregulation of DDAH expression and activity may be involved in this; however, knockout of DDAH1 does not modify the pathophysiological changes in remodeling of the pulmonary vasculature and the right ventricle.

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Angiotensin AT1receptor blockade fails to attenuate pressure-overload cardiac hypertrophy in fetal sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.4.r1501 ◽

1997 ◽

Vol 273 (4) ◽

pp. R1501-R1508 ◽

Cited By ~ 14

Author(s):

Jeffrey L. Segar ◽

Thomas D. Scholz ◽

Kurt A. Bedell ◽

Oliva M. Smith ◽

David J. Huss ◽

...

Keyword(s):

Body Weight ◽

Angiotensin Ii ◽

Left Ventricle ◽

Right Ventricle ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Pressure Overload ◽

Right Ventricular Hypertrophy ◽

Fetal Sheep ◽

Receptor Mrna

We examined the hypothesis that endogenous angiotensin II and angiotensin type 1 (AT1) receptors participate in the development of fetal right ventricular hypertrophy by studying the effects of AT1receptor blockade on cardiac growth in fetal sheep subjected to constrictive banding of the pulmonary artery (PA). Seven pairs of twin fetuses were studied beginning at 126 ± 1 days gestation (term = 145 days). One twin was given losartan (10 mg ⋅ kg−1⋅ day−1iv) for 7 consecutive days after PA banding, and the other twin served as a saline-treated, PA-banded control. Four additional pairs of twins served as sham-operated controls. Fetal heart rate (HR) and mean arterial blood pressure (MABP) were similar in the two groups of PA-banded animals before treatment and remained unchanged in the PA-banded control group. Losartan resulted in a significant decrease ( P < 0.05) in MABP between days 0 and 7, whereas HR was not affected. Total body weight of the losartan-treated animals was significantly less ( P < 0.05) than twin PA-banded controls and nonbanded fetuses. Right ventricle weight-to-body weight ratios were similar in saline (2.29 ± 0.34 g/kg) and losartan-treated (2.11 ± 0.15 g/kg) PA-banded animals and significantly greater than that in nonbanded fetuses (1.52 ± 0.07 g/kg). Similar differences were seen in the right ventricle weight-to-left ventricle weight ratios. Right and left ventricle AT1receptor mRNA and protein expression were also similar among the three groups, as were AT2receptor mRNA levels. These data suggest that endogenous angiotensin II does not contribute to the development of pressure overload-induced right ventricular hypertrophy during fetal life and that expression of angiotensin receptors is not altered by increased afterload in the ovine fetus.

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Bawei Chenxiang Wan Ameliorates Cardiac Hypertrophy by Activating AMPK/PPAR-α Signaling Pathway Improving Energy Metabolism

Frontiers in Pharmacology ◽

10.3389/fphar.2021.653901 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaoying Zhang ◽

Zhiying Zhang ◽

Pengxiang Wang ◽

Yiwei Han ◽

Lijun Liu ◽

...

Keyword(s):

Body Weight ◽

Energy Metabolism ◽

Cardiac Hypertrophy ◽

Heart Function ◽

Weight Ratio ◽

Tibetan Medicine ◽

Heart Weight ◽

Cardiomyocyte Hypertrophy ◽

Body Weight Ratio ◽

Cross Sectional

Bawei Chenxiang Wan (BCW), a well-known traditional Chinese Tibetan medicine formula, is effective for the treatment of acute and chronic cardiovascular diseases. In the present study, we investigated the effect of BCW in cardiac hypertrophy and underlying mechanisms. The dose of 0.2, 0.4, and 0.8 g/kg BCW treated cardiac hypertrophy in SD rat model induced by isoprenaline (ISO). Our results showed that BCW (0.4 g/kg) could repress cardiac hypertrophy, indicated by macro morphology, heart weight to body weight ratio (HW/BW), left ventricle heart weight to body weight ratio (LVW/BW), hypertrophy markers, heart function, pathological structure, cross-sectional area (CSA) of myocardial cells, and the myocardial enzymes. Furthermore, we declared the mechanism of BCW anti-hypertrophy effect was associated with activating adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK)/peroxisome proliferator–activated receptor-α (PPAR-α) signals, which regulate carnitine palmitoyltransferase1β (CPT-1β) and glucose transport-4 (GLUT-4) to ameliorate glycolipid metabolism. Moreover, BCW also elevated mitochondrial DNA-encoded genes of NADH dehydrogenase subunit 1(ND1), cytochrome b (Cytb), and mitochondrially encoded cytochrome coxidase I (mt-co1) expression, which was associated with mitochondria function and oxidative phosphorylation. Subsequently, knocking down AMPK by siRNA significantly can reverse the anti-hypertrophy effect of BCW indicated by hypertrophy markers and cell surface of cardiomyocytes. In conclusion, BCW prevents ISO-induced cardiomyocyte hypertrophy by activating AMPK/PPAR-α to alleviate the disturbance in energy metabolism. Therefore, BCW can be used as an alternative drug for the treatment of cardiac hypertrophy.

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Ventricular remodeling in a mouse model of myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.274.5.h1812 ◽

1998 ◽

Vol 274 (5) ◽

pp. H1812-H1820 ◽

Cited By ~ 62

Author(s):

Richard D. Patten ◽

Mark J. Aronovitz ◽

Luz Deras-Mejia ◽

Natesa G. Pandian ◽

George G. Hanak ◽

...

Keyword(s):

Myocardial Infarction ◽

Body Weight ◽

Mouse Model ◽

Sham Group ◽

Ventricular Remodeling ◽

Diastolic Pressure ◽

Weight Ratio ◽

Left Ventricular ◽

Body Weight Ratio ◽

Right Ventricular Mass

We investigated the suitability of studying ventricular remodeling in a mouse model of myocardial infarction (MI). We performed left coronary ligation ( n = 22) or a sham procedure ( n = 21) on normal C57BL/6J mice. Six weeks later, animals underwent echocardiography and hemodynamic evaluation. Left ventricular (LV) volume at a common distending pressure was calculated from passive pressure-volume curves. The MI group exhibited lower systolic blood pressure ( P < 0.05), higher LV end-diastolic pressure ( P < 0.05), and lower peak first derivative of LV pressure (dP/d t, P < 0.05) than the sham group. Mice with moderate (<40%, n = 11) and large (≥40%, n = 11) MIs displayed increased LV mass-to-body weight ratio ( P < 0.02 and P < 0.01, respectively, vs. sham group), whereas only the large-MI group exhibited increased right ventricular mass-to-body weight ratio ( P < 0.01). LV volumes were increased in the moderate-MI group ( P= 0.059 vs. sham group) and to a much greater extent in the large-MI group ( P < 0.0001 vs. sham group). The moderate- and large-MI groups also exhibited increases in LV end-diastolic diameter ( P < 0.03 and P < 0.0001, respectively, vs. sham group) and LV end-systolic diameter ( P< 0.01 and P < 0.0001, respectively, vs. sham group) with decreased fractional shortening ( P < 0.01 for both). These data demonstrate ventricular remodeling in a mouse model of MI and confirm the feasibility of quantifying indexes of remodeling in vivo and postmortem. This model will be of particular usefulness when applied to transgenic strains.

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P0875INFLUENCE OF CHRONIC KIDNEY DISEASE AND LEFT VENTRICULAR HYPERTROPHY ON CHANGE IN FGF23 AND RENIN-ANGIOTENSIN-ALDOSTERONE-SYSTEM

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa143.p0875 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Kohei Okamoto ◽

Hideki Fujii ◽

Shunsuke Goto ◽

Keiji Kono ◽

Kentaro Watanabe ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Body Weight ◽

Mrna Expression ◽

Ventricular Hypertrophy ◽

Weight Ratio ◽

Left Ventricular ◽

Heart Weight ◽

Control Group ◽

Body Weight Ratio ◽

Related Factors

Abstract Background and Aims Left ventricular hypertrophy (LVH) is a clinically important risk factor for mortality and often observed in patients with chronic kidney disease (CKD). Serum FGF23 levels are elevated in CKD patients, and the relationship between elevated FGF23 and LVH has been reported in the previous studies. However, whether elevated FGF23 is a cause or result of LVH and whether FGF23 directly or indirectly affects LVH remain unclear. Therefore, we investigated changes in heart weight, CKD-mineral and bone disorder (MBD) parameters, including FGF23, and renin-angiotensin-aldosterone system (RAAS) related-factors in the setting of LVH and CKD using a mouse model. Method In the present study, twenty-four C57BL/6J mice were used and divided into 4 groups; control group (N=6), CKD group (N=6), LVH group (N=6), and LVH+CKD group (N=6). The mice in the CKD group underwent left 2/3 nephrectomy at 11 weeks of age and right nephrectomy at 12 weeks of age. Those in the LVH group underwent transverse aortic constriction (TAC) at 10 weeks of age. Those in the LVH+CKD group, TAC at 10 weeks of age, and left 2/3 nephrectomy at 11 weeks of age, and right nephrectomy at 12 weeks of age were performed. At 16 weeks of age, echocardiography was performed for all the mice, and they were sacrificed for blood and urine analysis, histopathological analysis and evaluating mRNA expressions of CKD-MBD- and RAAS-related factors in the heart. Results The systolic blood pressure was significantly higher in the LVH+CKD group and the CKD group than in the control group. The heart weight/body weight ratio in the LVH+CKD group was the highest, and that in the LVH was higher than that in the CKD group. Although serum creatinine and phosphate levels increased in CKD condition, those were comparable between the CKD and LVH+CKD groups. The urinary albumin excretion also increased in the CKD and LVH+CKD groups compared to the LVH and control groups. Serum FGF23 levels increased in the LVH and CKD group compared to the control group, and those in the LVH+CKD group were the highest among all the study groups. The cardiac mRNA expressions of FGF23, angiotensinogen (ANG), angiotensin type 1 receptor (AT1R), and angiotensin-converting enzyme (ACE) were also increased by induction of LVH and CKD, and those in the LVH+CKD group significantly increased compared to other groups. Heart weight/body weight ratio was significantly correlated with serum FGF23 levels and mRNA expression of FGF23, ANG, AT1R, ACE. In addition, significant correlations of serum FGF23 levels and cardiac mRNA expression of FGF23 with cardiac mRNA expressions of RAAS-related factors were observed. Conclusion Our results suggest that serum FGF23 levels and cardiac mRNA expression of FGF23 increase with the development of LVH and CKD and the changes is possibly enhanced through the colocalized activation of RAAS.

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Lower Body Weight in Rats Under Hypobaric Hypoxia Exposure Would Lead to Reduced Right Ventricular Hypertrophy and Increased AMPK Activation

Frontiers in Physiology ◽

10.3389/fphys.2020.00342 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Karen Flores ◽

Patricia Siques ◽

Julio Brito ◽

Stefany Ordenes ◽

Karem Arriaza ◽

...

Keyword(s):

Body Weight ◽

Right Ventricular ◽

Hypobaric Hypoxia ◽

Ventricular Hypertrophy ◽

Right Ventricular Hypertrophy ◽

Lower Body ◽

Ampk Activation ◽

Hypoxia Exposure ◽

Lower Body Weight

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The hypertrophic heart rat: a new normotensive model of genetic cardiac and cardiomyocyte hypertrophy

Physiological Genomics ◽

10.1152/physiolgenomics.00006.2002 ◽

2002 ◽

Vol 9 (1) ◽

pp. 43-48 ◽

Cited By ~ 19

Author(s):

Stephen B. Harrap ◽

Vennetia R. Danes ◽

Justine A. Ellis ◽

Cory D. Griffiths ◽

Elizabeth F. Jones ◽

...

Keyword(s):

Blood Pressure ◽

Body Weight ◽

Ventricular Hypertrophy ◽

Weight Ratio ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Spontaneously Hypertensive ◽

Fischer 344 ◽

Lv Mass ◽

Low Blood Pressure

We describe a new line of rats with inherited cardiomyocyte and ventricular hypertrophy. From a second-generation cross of spontaneously hypertensive and Fischer 344 rats, we selected for low blood pressure and either high or low echocardiographic left ventricular (LV) mass over four generations to establish the hypertrophic heart rat (HHR) and normal heart rat (NHR) lines, respectively. After 13 generations of inbreeding, HHR had significantly greater ( P < 0.0001) LV mass-to-body weight ratio (2.68 g/kg, SE 0.14) than NHR matched for age (1.94 g/kg, SE 0.02) or body weight (2.13 g/kg, SE 0.03). The isolated cardiomyocytes of HHR were significantly ( P < 0.0001) longer and wider (161 μm, SE 0.83; 35.6 μm, SE 2.9) than NHR (132 μm, SE 1.2; 29.5 μm, SE 0.35). Telemetric 24-h recordings of mean arterial pressure revealed no significant differences between HHR and NHR. The HHR offers a new model of primary cardiomyocyte hypertrophy with normal blood pressure in which to examine genotypic causes and pathogenetic mechanisms of hypertrophy and its complications.

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ANG II receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.6.h2468 ◽

1994 ◽

Vol 266 (6) ◽

pp. H2468-H2475 ◽

Cited By ~ 13

Author(s):

H. A. Rockman ◽

S. P. Wachhorst ◽

L. Mao ◽

J. Ross

Keyword(s):

Body Weight ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Ventricular Hypertrophy ◽

Systolic Pressure ◽

Weight Ratio ◽

Pressure Overload ◽

Heart Weight ◽

Receptor Blockade ◽

Body Weight Ratio

There is increasing evidence that the renin-angiotensin system may play a important role in cardiac hypertrophy. To assess the role of angiotensin II in the induction of cardiac hypertrophy, three groups of adult mice were subjected to left ventricular pressure overload by transverse aortic constriction (TAC). For the next 7 days the groups received either the specific angiotensin II subtype 1 receptor (AT1) antagonist (losartan, 1.05 g/l; n = 17), an angiotensin enzyme inhibitor (captopril, 2 g/l; n = 17), or no treatment (n = 22) administered in the drinking water and compared with three similarly treated sham-operated groups (n = 7 each). TAC resulted in a significant increase in heart weight-to-body weight ratio (0.634 +/- 0.087 vs. 0.525 +/- 0.039, g/g x 100, P < 0.05), which was prevented by losartan (0.506 +/- 0.069, g/g x 100, P < 0.0001) despite similar hemodynamic load (proximal systolic pressure 146 +/- 31 vs. 136 +/- 32 mmHg, untreated vs. losartan, P = NS). Proximal systolic pressure was positively correlated with the development of ventricular hypertrophy. In the presence of AT1-receptor blockade, the increase in heart weight-to-body weight ratio at any given systolic pressure was significantly attenuated compared with untreated TAC mice. The increase in heart weight-to-body weight ratio was also significantly attenuated by captopril compared with untreated banded controls (0.542 +/- 0.091, g/g x 100, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

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