Impact of acute antioxidant administration on inflammation and vascular function in heart failure with preserved ejection fraction

Ratchford, Stephen M.; Clifton, Heather L.; Gifford, Jayson R.; LaSalle, David Taylor; Thurston, Taylor S.; Bunsawat, Kanokwan; Alpenglow, Jeremy K.; Richardson, Russell S.; Wright, Josephine; Ryan, John; Wray, D. Walter

doi:10.1152/ajpregu.00184.2019

Cited by 17 publications

(21 citation statements)

References 45 publications

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“…A pro-inflammatory state that leads to the pathophysiology of HFpEF has been recently emphasized ( Paulus and Tschope, 2013 ; van Empel and Brunner-La Rocca, 2015 ; van Sanders-Wijk et al, 2015 ; Riba et al, 2017 ; Ratchford et al, 2019 ). We were interested in determining whether RES can decrease HFpEF-induced cardiac inflammatory response.…”

Section: Resultsmentioning

confidence: 99%

Resveratrol Ameliorates Cardiac Remodeling in a Murine Model of Heart Failure With Preserved Ejection Fraction

et al. 2021

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Objective: Accumulating evidence suggested that resveratrol (RES) could protect against adverse cardiac remodeling induced by several cardiovascular diseases. However, the role of RES in the setting of heart failure with preserved ejection fraction (HFpEF) and the underlying mechanisms of its action remain understood. This study was to determine whether RES could ameliorate HFpEF-induced cardiac remodeling and its mechanisms.Methods:In vivo, C57BL/6 mice served as either the sham or the HFpEF model. The HFpEF mice model was induced by uninephrectomy surgery and d-aldosterone infusion. RES (10 mg/kg/day, ig) or saline was administered to the mice for four weeks. In vitro, transforming growth factor β1 (TGF-β1) was used to stimulate neonatal rat cardiac fibroblasts (CFs) and Ex-527 was used to inhibit sirtuin 1 (Sirt1) in CFs. Echocardiography, hemodynamics, western blotting, quantitative real-time PCR, histological analysis, immunofluorescence, and ELISA kits were used to evaluate cardiac remodeling induced by HFpEF. Sirt1 and Smad3 expressions were measured to explore the underlying mechanisms of RES.Results: HFpEF mice developed left ventricular hypertrophy, preserved ejection fraction, diastolic dysfunction, and pulmonary congestion. Moreover, HFpEF mice showed increased infiltration of neutrophils and macrophages into the heart, including increased interleukin (IL)-1β, IL-6, and TNF-α. We also observed elevated M1 macrophages and decreased M2 macrophages, which were exhibited by increased mRNA expression of M1 markers (iNOS, CD86, and CD80) and decreased mRNA expression of M2 markers (Arg1, CD163, and CD206) in HFpEF hearts. Moreover, HFpEF hearts showed increased levels of intracellular reactive oxygen species (ROS). Importantly, HFpEF mice depicted increased collagen-I and -III and TGF-β mRNA expressions and decreased protein expression of phosphorylated endothelial nitric-oxide synthase (p-eNOS). Results of western blot revealed that the activated TGF-β/Smad3 signaling pathway mediated HFpEF-induced cardiac remodeling. As expected, this HFpEF-induced cardiac remodeling was reversed when treated with RES. RES significantly decreased Smad3 acetylation and inhibited Smad3 transcriptional activity induced by HFpEF via activating Sirt1. Inhibited Sirt1 with Ex-527 increased Smad3 acetylation, enhanced Smad3 transcriptional activity, and offset the protective effect of RES on TGF-β–induced cardiac fibroblast–myofibroblast transformation in CFs.Conclusion: Our results suggested that RES exerts a protective action against HFpEF-induced adverse cardiac remodeling by decreasing Smad3 acetylation and transcriptional activity via activating Sirt1. RES is expected to be a novel therapy option for HFpEF patients.

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Section: Resultsmentioning

confidence: 99%

Resveratrol Ameliorates Cardiac Remodeling in a Murine Model of Heart Failure With Preserved Ejection Fraction

et al. 2021

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“…Fortunately, there is evidence for the ‘reversibility’ of vascular dysfunction associated with elevated oxidative stress. Indeed, our group has demonstrated the efficacy of acute oral AOx administration to improve brachial artery FMD and favourably affect both oxidative stress and endogenous AOx capacity in several cohorts, including the elderly (Wray et al., 2012) and patients with chronic obstructive pulmonary disease (Ives et al., 2014; Rossman et al., 2013) or heart failure with preserved ejection fraction (Ratchford et al., 2019). Conversely, we recently demonstrated that acute AOx administration does not improve FMD in patients with HFrEF (Witman et al., 2012a), suggesting that perhaps a longer duration of AOx administration, as conducted in this investigation, might be warranted.…”

Section: Discussionmentioning

confidence: 99%

“…Fortunately, there is evidence for the 'reversibility' of vascular dysfunction associated with elevated oxidative stress. Indeed, our group has demonstrated the efficacy of acute oral AOx administration to improve brachial artery FMD and favourably affect both oxidative stress and endogenous AOx capacity in several cohorts, including the elderly (Wray et al, 2012) and patients with chronic obstructive pulmonary disease (Ives et al, 2014;Rossman et al, 2013) or heart failure with preserved ejection fraction (Ratchford et al, 2019).…”

Section: Mechanisms Of Vascular Dysfunction In Patients With Hfrefmentioning

confidence: 96%

“…Evidence from our group (Witman et al., 2012a, b) and others (Ellis et al., 2000; Tsutsui, Kinugawa, & Matsushima, 2011) has collectively demonstrated a marked increase in oxidative stress in patients with HFrEF, but strategies for mitigating this maladaptation are less well studied. One such approach is AOx administration, which we have used previously in several populations to target oxidative stress acutely and improve antioxidant capacity and vascular function, including the elderly (Wray et al., 2012) and patients with chronic obstructive pulmonary disease (Ives et al., 2014) and heart failure with preserved ejection fraction (Ratchford et al., 2019). Interestingly, acute AOx administration failed to improve macro‐ and microvascular function in patients with HFrEF, as assessed by FMD and RH, respectively (Witman et al., 2012a), suggesting that perhaps a longer duration of AOx treatment might be needed to improve overall vascular health in this patient group.…”

Section: Introductionmentioning

confidence: 99%

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Chronic antioxidant administration restores macrovascular function in patients with heart failure with reduced ejection fraction

Bunsawat

Ratchford

Alpenglow

et al. 2020

Experimental Physiology

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Heart failure with reduced ejection fraction (HFrEF) is characterized by macrovascular dysfunction and elevated oxidative stress that may be mitigated by antioxidant (AOx) administration. In this prospective study, we assessed flow-mediated dilatation (FMD) and reactive hyperaemia responses in 14 healthy, older control participants and 14 patients with HFrEF, followed by 30 days of oral AOx administration (1 g vitamin C, 600 I.U. vitamin E and 0.6 g α-lipoic acid) in the patient group. Blood biomarkers of oxidative stress (malondialdehyde) and AOx capacity (ferric reducing ability of plasma) were also assessed. Patients with HFrEF had a lower %FMD (2.63 ± 1.57%) than control participants (5.62 ± 2.60%), and AOx administration improved %FMD in patients with HFrEF (30 days, 4.90 ± 2.38%), effectively restoring macrovascular function to that of control participants. In a subset of patients, we observed a progressive improvement in %FMD across the treatment period (2.62 ± 1.62, 4.23 ± 2.69, 4.33 ± 2.24 and 4.97 ± 2.56% at days 0, 10, 20 and 30, respectively, n = 12) that was abolished 7 days after treatment cessation (2.99 ± 1.78%, n = 9). No difference in reactive hyperaemia was evident between groups or as a consequence of the AOx treatment. Ferric reducing ability of plasma levels increased (from 6.08 ± 2.80 to 6.70 ± 1.59 mM, day 0 versus 30) and malondialdehyde levels decreased (from 6.81 ± 2.80 to 6.22 ± 2.84 μM, day 0 versus 30) after treatment. These findings demonstrate the efficacy of chronic AOx administration in attenuating oxidative stress, improving AOx capacity and restoring macrovascular function in patients with HFrEF.

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“…The value of fractional shortening (FS) is widely used to assess left ventricular dysfunction and often decreased after myocarditis [9]. On the other hand, preserved EF [10] is associated with predominant inflammation and oxidant stress.…”

Section: Introductionmentioning

confidence: 99%

Chitoheptaose Promotes Heart Rehabilitation in a Rat Myocarditis Model by Improving Antioxidant, Anti-Inflammatory, and Antiapoptotic Properties

Zhao

Yin²,

Zhang³

et al. 2020

Oxidative Medicine and Cellular Longevity

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Background. Myocarditis is one of the important causes of dilated cardiomyopathy, cardiac morbidity, and mortality worldwide. Chitosan oligosaccharides (COS) may have anti-inflammatory and cardioprotective effects on myocarditis. However, the exact molecular mechanism for the effects of functional COS on myocarditis remains unclear. Methods. Antiinflammatory activities of COS (chitobiose, chitotriose, chitotetraose, chitopentaose, chitohexaose, chitoheptaose, and chitooctaose) were measured in lipopolysaccharide-(LPS-) stimulated RAW264.7 cells. A rat model with myocarditis was established and treated with chitopentaose, chitohexaose, chitoheptaose, and chitooctaose. Serum COS were measured by using high-performance liquid chromatography (HPLC) in all rats. Myocarditis injury, the levels of reactive oxygen species (ROS), reactive nitrogen species (RNS), inflammatory factors, and apoptotic factors were also measured. Pearson's correlation coefficient test was used to explore the relationship between the levels of ROS/RNS and cardiac parameters. Results. Among all chitosan oligosaccharides, the COS > degrees of polymerization ðDPÞ 4 showed anti-inflammatory activities (the activity order was chitopentaose 4). The levels of ROS/RNS had a strong relationship with cardiac parameters. Conclusions. Chitoheptaose plays a myriad of cardioprotective roles in the myocarditis model via its antioxidant, anti-inflammatory, and antiapoptotic activities.

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Impact of acute antioxidant administration on inflammation and vascular function in heart failure with preserved ejection fraction

Cited by 17 publications

References 45 publications

Resveratrol Ameliorates Cardiac Remodeling in a Murine Model of Heart Failure With Preserved Ejection Fraction

Resveratrol Ameliorates Cardiac Remodeling in a Murine Model of Heart Failure With Preserved Ejection Fraction

Chronic antioxidant administration restores macrovascular function in patients with heart failure with reduced ejection fraction

Chitoheptaose Promotes Heart Rehabilitation in a Rat Myocarditis Model by Improving Antioxidant, Anti-Inflammatory, and Antiapoptotic Properties

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