scholarly journals Angiotensin-II type 1 receptor mediates pulmonary hypertension and right ventricular remodeling induced by inhaled nicotine.

2021 ◽  
Author(s):  
Nicholas D. Fried ◽  
Tamara M. Morris ◽  
Anna Whitehead ◽  
Eric Lazartigues ◽  
Xinping Yue ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Angiotensin Ii ◽  
Right Ventricular ◽  
Ventricular Remodeling ◽  
Electronic Cigarettes ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Serum Cotinine

Use of electronic cigarettes is rapidly increasing among youth and young adults, but little is known regarding the long-term cardiopulmonary health impacts of these nicotine-containing devices. Our group has previously demonstrated that chronic, inhaled nicotine induces pulmonary hypertension (PH) and right ventricular (RV) remodeling in mice. These changes were associated with upregulated RV angiotensin-converting enzyme (ACE). Angiotensin-II receptor blockers (ARBs) have been shown to reverse cigarette smoking-induced PH in rats. ACE inhibitor and ARB use in a large retrospective PH patient cohort is associated with improved survival. Here, we utilized losartan (an ARB specific for angiotensin-II type 1 receptor) to further explore nicotine-induced PH. Male C57BL/6 mice received nicotine vapor for 12 hours per day, and exposure was assessed using serum cotinine to achieve levels comparable to human smokers or electronic cigarette users. Mice were exposed to nicotine for 8 weeks and a subset was treated with losartan via osmotic minipump. Cardiac function was assessed using echocardiography and catheterization. Although nicotine exposure increased angiotensin-II in the RV and lung, this finding was non-significant. Chronic, inhaled nicotine significantly increased RV systolic pressure and RV free wall thickness versus air control. These parameters were significantly lower in mice receiving both nicotine and losartan. Nicotine significantly increased RV internal diameter, with no differences seen between the nicotine and nicotine-losartan group. Neither nicotine nor losartan effect left ventricular structure or function. These findings provide the first evidence that antagonism of the angiotensin-II type 1 receptor can ameliorate chronic, inhaled nicotine-induced PH and RV remodeling.

scholarly journals Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension

2009 ◽  
Vol 296 (6) ◽  
pp. H2007-H2014 ◽  
Author(s):  
Inês Falcão-Pires ◽  
Nádia Gonçalves ◽  
Tiago Henriques-Coelho ◽  
Daniel Moreira-Gonçalves ◽  
Roberto Roncon-Albuquerque ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pressure Rise ◽  
Chronic Administration ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Peak Rate ◽  
Male Wistar Rats ◽  
Neurohumoral Activation

We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle ( day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 μg·kg−1·day−1 ip) or a similar volume of saline, resulting in four groups: sham ( n = 11), sham-AP ( n = 11), MCT ( n = 16), and MCT-AP ( n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 ± 38%), diameter of cardiomyocyte (40 ± 10%), myocardial fibrosis (95 ± 20%), peak systolic pressure (99 ± 22%), peak rate of ventricular pressure rise (dP/d tmax; 74 ± 24%), peak rate of ventricular pressure decline (dP/d tmin; 73 ± 19%), and time constant τ (55 ± 16%). In these animals, RV expression of apelin (−73 ± 10%) and its receptor APJ (−61 ± 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 ± 713%), angiotensinogen (191 ± 147%), endothelin-1 (RV, 497 ± 156%; and LV, 799 ± 309%), plasmatic levels of apelin (104 ± 48%), and angiotensin 1-7 (161 ± 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.

Abstract 13973: Impaired Right Ventricular Hemodynamics Suggest Preclinical Pulmonary Hypertension in Patients With Metabolic Syndrome

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Deepa M Gopal ◽  
Yi-Chih Wang ◽  
Nir Ayalon ◽  
Courtney Donohue ◽  
Rajalakshmi Santhanakrishnan ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Systolic Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Doppler Measurement ◽  
Ejection Time ◽  
Pulsed Wave Doppler ◽  
Lv Diastolic Dysfunction

Introduction: Metabolic syndrome (MetS) is associated with preclinical metabolic heart disease (MHD) as reflected by left ventricular (LV) diastolic dysfunction. Very little is known about right ventricular (RV) function and/or pulmonary hypertension in MetS or early MHD. Hypothesis: We tested the hypothesis that that MetS is associated with subclinical RV dysfunction and pulmonary hypertension. Methods: A total of 164 subjects with MetS but without cardiovascular disease (mean age 45 years, 71% women, mean BMI 41 kg/m 2 ), 40 similarly obese controls without MetS, and 36 non-obese healthy controls underwent echocardiography, including pulsed-wave Doppler measurement of pulmonary artery acceleration time (PAAT) and ejection time (ET). PA systolic pressure was estimated from PAAT using validated equations. Results: MetS was associated with lower tricuspid valve e', shorter PAAT, shorter ET, and larger PA diameter compared with controls (Table). A total of 24% of individuals with MetS had an abnormal PAAT (<100 msec). Estimated PA systolic pressure based on PAAT was 42±10 mmHg in MetS compared with 32±10 and 32±9 mmHg in healthy and obese controls (P for ANOVA <0.0001). In contrast, RV structure and systolic function were similar in MetS compared with controls ( Table ). After adjustment for age, sex, hypertension, diabetes, and body-mass index, MetS remained associated with shorter PAAT (P=0.03 vs healthy; P=0.0005 vs obese). Among MetS, PAAT was correlated with mitral mean e’ (r=0.20, P=0.004), E/A ratio (r=0.21, P=0.008), and tricuspid e’ (r=0.20, P=0.04). A total of 40% of participants with abnormal PAAT also had low mean e’ (<8 cm/s). Conclusions: MetS is associated with abnormal RV hemodynamics as evidenced by shorter PAAT, which correlates with measures of LV diastolic function. Estimated PA systolic pressures are significantly higher in preclinical MetS and MHD, and raise the possibility that pulmonary hypertension contributes to the pathophysiology of MHD.

Osteopontin and galectin-3 as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension

2021 ◽  
Author(s):  
Stanislav Keranov ◽  
Oliver Dörr ◽  
Leili Jafari ◽  
Christoph Liebetrau ◽  
Till Keller ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Dilated Cardiomyopathy ◽  
Ventricular Hypertrophy ◽  
Ventricular Remodeling ◽  
Left Ventricular ◽  
Potential Biomarker ◽  
Lv Remodeling ◽  
Galectin 3 ◽  
Right Ventricular Remodeling

Aim: This study assessed the utility of osteopontin (OPN) and galectin-3 (Gal-3) as biomarkers of maladaptive right ventricular remodeling in pulmonary hypertension (PH). Materials & methods: We examined plasma levels of OPN and Gal-3 in patients with PH (n = 62), dilated cardiomyopathy (n = 34), left ventricular hypertrophy (LVH; n = 47), and controls without right ventricle (RV) or LV abnormalities (n = 38). Results: OPN and Gal-3 levels were higher in PH, dilated cardiomyopathy and LVH than in the controls. OPN concentrations in PH patients with maladaptive RV were significantly higher than in those with adaptive RV. Gal-3 did not differentiate between adaptive and maladaptive RV remodeling in PH. OPN and Gal-3 levels did not correlate with parameters of LV remodeling. Conclusion: OPN is a potential biomarker of RV maladaptation.

Agonist-independent Activation of the Angiotensin II Type 1 Receptor Contributes to Left Ventricular Remodeling in vivo

2009 ◽  
Vol 15 (7) ◽  
pp. S151-S152
Author(s):  
Noritaka Yasuda ◽  
Hiroshi Akazawa ◽  
Kaoru Ito ◽  
Yoko Kudo ◽  
Issei Komuro
Keyword(s):  
Angiotensin Ii ◽  
Ventricular Remodeling ◽  
Left Ventricular Remodeling ◽  
Left Ventricular

scholarly journals Exposure to diesel exhaust particulates induces cardiac dysfunction and remodeling

2013 ◽  
Vol 115 (7) ◽  
pp. 1099-1106 ◽  
Author(s):  
Jessica M. Bradley ◽  
Kipp A. Cryar ◽  
Milad C. El Hajj ◽  
Elia C. El Hajj ◽  
Jason D. Gardner
Keyword(s):  
Diesel Exhaust ◽  
Ventricular Remodeling ◽  
Diastolic Pressure ◽  
Hypoxia Inducible Factor ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Ventricular Dilation ◽  
Hypoxia Inducible Factor 1Α ◽  
Left Ventricular Dilation

Chronic exposure to diesel exhaust particulates (DEP) increases the risk of cardiovascular disease in urban residents, predisposing them to the development of several cardiovascular stresses, including myocardial infarctions, arrhythmias, thrombosis, and heart failure. DEP contain a high level of polycyclic aromatic hydrocarbons, which activate the aryl hydrocarbon receptor (AHR). We hypothesize that exposure to DEP elicits ventricular remodeling through the activation of the AHR pathway, leading to ventricular dilation and dysfunction. Male Sprague-Dawley rats were exposed by nose-only nebulization to DEP (SRM 2975, 0.2 mg/ml) or vehicle for 20 min/day × 5 wk. DEP exposure resulted in eccentric left ventricular dilation (8% increased left ventricular internal diameter at diastole and 23% decreased left ventricular posterior wall thickness at diastole vs. vehicle), as shown by echocardiograph assessment. Histological analysis using Picrosirius red staining revealed that DEP reduced cardiac interstitial collagen (23% decrease vs. vehicle). Further assessment of cardiac function using a pressure-volume catheter indicated impaired diastolic function (85% increased end-diastolic pressure and 19% decreased Tau vs. vehicle) and contractility (57 and 48% decreased end-systolic pressure-volume relationship and maximum change in pressure over time vs. end-diastolic volume compared with vehicle, respectively) in the DEP-exposed animals. Exposure to DEP significantly increased cardiac expression of AHR (19% increase vs. vehicle). In addition, DEP significantly decreased the cardiac expression of hypoxia inducible factor-1α, the competitive pathway to the AHR, and vascular endothelial growth factor, a downstream mediator of hypoxia inducible factor-1α (26 and 47% decrease vs. vehicle, respectively). These findings indicate that exposure to DEP induced left ventricular dilation by loss of collagen through an AHR-dependent mechanism.

scholarly journals Tofogliflozin improved pulmonary hypertension due to heart failure with preserved ejection fraction in mice

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
Y J Joki ◽  
H K Konishi ◽  
K T Takasu ◽  
T M Minamino
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Right Ventricular ◽  
Heart Diseases ◽  
Sglt2 Inhibitor ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Chow Diet ◽  
Normal Chow

Abstract Introduction Pulmonary hypertension (PH) caused by left heart diseases is categorized as the group 2 (PH-LHD). PH-LHD due to heart failure with preserved LV ejection fraction (HFpEF) is more prevalent in patients with metabolic syndrome and shows poorer prognosis than LHD without PH. Tofogliflozin (TOFO) is an SGLT2 inhibitor utilized for diabetic treatment. Recent studies revealed that the SGLT2 inhibitor has a beneficial effect on heart failure; however, it remains unclear whether the SGLT2 inhibitor is effective for the treatment of PH-LHD. Hypothesis We hypothesized that TOFO has a protective effect on PH with HFpEF. Methods We generated two murine models for PH-LHD due to HFpEF, a transverse aortic constriction (TAC) model and a high fat diet (HFD) model. C57BL/6J mice were subjected to TAC and treated with TOFO (3 mg/kg) for 4weeks. In another model, AKR/J mice were fed HFD or normal chow diet and treated with TOFO (3mg/kg in water) for 20 weeks. We then measured physical data including body weight (BW), left ventricular weight (LV), right ventricular weight (RV), and right ventricular systolic pressure (RVSP) and performed echocardiography. Results Mice treated with TOFO demonstrated increased urine glucose level. TAC induced left ventricular hypertrophy and increased RVSP. TOFO treatment improved RV/LV ratio and RVSP in TAC mice (Figure 1). HFD fed AKR/J mice demonstrated increased BW and PH as demonstrated by increased RV/LV ratio and RVSP compared with the normal chow group. TOFO treatment ameliorated the increases of BW, RV/LV ratio, and RVSP in HFD fed AKR/J mice (Figure 2). Conclusions TOFO treatment improved pulmonary hypertension in two models for PH-LHD due to HFpEF, suggesting that the SGLT2 inhibitor is effective for the treatment of this condition. FUNDunding Acknowledgement Type of funding sources: None. Figure 2. TOFO reduced RVSP caused by HFD

Abstract 230: Gender Differences in the Development of Experimental Pulmonary Hypertension and Associated Right Ventricular Remodeling: The Role of Estrogen Rescue

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Soban Umar ◽  
Rangarajan Nadadur ◽  
Mansoureh Eghbali
Keyword(s):  
Gender Differences ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Ventricular Remodeling ◽  
Therapeutic Potential ◽  
Systolic Pressure ◽  
Female Rats ◽  
Male And Female ◽  
Male And Female Rats ◽  
Ovx Rats

17-beta estradiol or Estrogen (E2) pre-treatment has been shown to attenuate the development of pulmonary hypertension (PH). Here, we aim to investigate the gender differences and the effect of ovariectomy on the development of experimental PH and adverse right ventricular (RV) remodeling. We also evaluate the therapeutic potential of E2 in rescuing PH and adverse RV remodelling in male and female rats. Male and female (intact and ovariectomized (OVX)) rats were treated with a single injection of monocrotaline (MCT, 60mg/kg, s.c.) to induce PH. Twenty one days after MCT, rats developed severe PH. At this point, one set of rats from each group was left untreated to develop PH-induced right ventricular failure (RVF), whereas the other set received E2 (42.5 ug/kg/day, 10-day slow release s.c. pellets). E2-treated rats were observed for an additional 12 days after cessation of therapy to check whether the effects of therapy were long-lived. Saline treated rats served as control (CTRL). Serial echocardiography was performed to monitor cardiopulmonary hemodynamics. Direct RV catheterization was terminally performed to record RV peak systolic pressure (RVPSP). The expression of novel extracellular matrix (ECM) enzymes A Disintegrin And Metalloproteinase (ADAM15 and 17) and Osteopontin (OPN) were assessed by RT-PCR. Intact females developed less severe PH than males and OVX females at day 30 (RVPSP: Females=62±3, Males=74±3, OVX=77±3 mm Hg, p<0.05 vs. respective CTRL). E2 therapy resulted in rescue of PH in all groups (RVPSP: Females=36±4, Males=38±2, OVX=44±2 mm Hg, p<0.05 vs. respective PH-RVF). Intact females also developed less severe RV remodeling compared to males and OVX females. Expression of OPN increased ∼7-9-fold in PH-RVF males and OVX but only ∼2-fold in intact females, (p<0.05 vs. CTRL for all). E2 reversed OPN upregulation in all groups (p<0.05 vs. PH-RVF). Novel ECM-degrading Disintegrin-Metalloproteinases ADAM15 and ADAM17 transcripts were also elevated ∼2-fold in all PH-RVF animals (p<0.05 vs. CTRL). E2-therapy reversed RV remodeling in all groups (p<0.05 vs. PH-RVF). In conclusion, intact females are more protected against the development of PH compared to males and OVX females. E2 rescues PH and adverse RV remodeling in all groups.

Abstract 16307: Tofogliflozin Improves Pulmonary Hypertension With Heart Failure With Preserved Ejection Fraction Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yusuke Joki ◽  
Hakuoh Konishi ◽  
Kiyoshi Takasu ◽  
Tohru Minamino
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Beneficial Effect ◽  
Right Ventricular ◽  
Sglt2 Inhibitor ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Urine Glucose

Introduction: Pulmonary hypertension (PH) is a syndrome of increased pulmonary artery pressure and often leads to death. Left heart diseases(LHD) are frequently complicated by PH (PH-LHD), classified group2. In particular, PH with heart failure with preserved LV ejection fraction (HFpEF) is higher prevalence metabolic syndrome and poor prognosis than LHD without PH. Tofogliflozin (TOFO) is SGLT2 inhibitor as a therapeutic agent for diabetes. Recent study revealed SGLT2 inhibitors have a beneficial effect on heart failure. However it has not been clarified that SGLT2 inhibitors affect PH-LHD. This study examined whether TOFO improved for PH-LHD. Hypothesis: We hypothesis TOFO has a protective effect for PH with HFpEF. Methods: We used two HFpEF mice models, induced by transverse aortic constriction (TAC) surgery and high fat diet (HFD). TAC model: C57BL/6J mice were subjected to TAC. Sham and TAC mice were treated with TOFO 3mg/kg in water by day or only water. After 4weeks, each mouse was measured physical data, Body weight (BW), Left ventricular weight (LV), Right ventricular weight (RV), right ventricular systolic pressure (RVSP), UCG, collected blood and urine glucose. HFD model: AKR/J mice fed a HFD for 20weeks. Regular diet and HFD mice were treated with TOHO 3mg/kg in water by day or only water. 20weeks later each mouse measured above data. Results and Conclusions: Mice treated with TOFO had significantly higher urine glucose concentrations. TAC induced left ventricular hypertrophy, increased HW/BW ratio and RVSP. However TAC+TOFO mice were reduced hypertrophy and LV/BW ratio than TAC group. Moreover TAC+TOFO mice were improved RV/LV ratio and RVSP (Figure). AKR/J+HFD groups substantially higher BW and occurred PH than RFD groups. In contrast with HFD, TOFO treated group ameliorated BW, RW/LW ratio, moreover normal RVSP. These results showed Tofogliflozin had a beneficial effect for PH with HFpEF.

scholarly journals PKG-1α leucine zipper domain defect increases pulmonary vascular tone: implications in hypoxic pulmonary hypertension

2014 ◽  
Vol 307 (7) ◽  
pp. L537-L544 ◽  
Author(s):  
Ramaswamy Ramchandran ◽  
Aarti Raghavan ◽  
David Geenen ◽  
Miranda Sun ◽  
Laura Bach ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Vascular Tone ◽  
Leucine Zipper ◽  
Ventricular Remodeling ◽  
Systolic Pressure ◽  
Progressive Increase ◽  
Leucine Zipper Domain ◽  
Phosphodiesterase 5

Pulmonary hypertension (PH) is a chronic disease characterized by a progressive increase in vasomotor tone, narrowing of the vasculature with structural remodeling, and increase in pulmonary vascular resistance. Current treatment strategies include nitric oxide therapy and methods to increase cGMP-mediated vasodilatation. cGMP-dependent protein kinases (PKG) are known mediators of nitric oxide- and cGMP-induced vasodilatation. Deletion of PKG-1 in mice has been shown to induce PH, however, the exact mechanisms by which loss of PKG-1 function leads to PH is not known. In a mouse model with a selective mutation in the NH2-terminus leucine zipper protein interaction domain of PKG-1α [leucine zipper mutant (LZM)], we found a progressive increase in right ventricular systolic pressure and right heart hypertrophy compared with wild-type (WT) mice and increased RhoA-GTPase activity in the lungs. When exposed to chronic hypoxia, LZM mice developed modestly enhanced right ventricular remodeling compared with WT mice. Tadalafil, a phosphodiesterase-5 inhibitor that increases cGMP levels, significantly attenuated hypoxia-induced cardiopulmonary remodeling in WT mice but had no effect in LZM mice. We conclude that a functional leucine zipper domain in PKG-1α is essential for maintenance of a low pulmonary vascular tone in normoxia and for cGMP-mediated beneficial effects of phosphodiesterase-5 inhibition in hypoxic cardiopulmonary remodeling.

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