Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan 20;132(2):154-166.
doi: 10.1161/CIRCRESAHA.122.321326. Epub 2022 Dec 28.

Hydrogen Sulfide Modulates Endothelial-Mesenchymal Transition in Heart Failure

Zhen Li  1 , Huijing Xia  2 , Thomas E Sharp 3rd  2 , Kyle B LaPenna  2 , Antonia Katsouda  3 , John W Elrod  4 , Josef Pfeilschifter  5 , Karl-Friedrich Beck  5 , Shi Xu  6 , Ming Xian  6 , Traci T Goodchild  2 , Andreas Papapetropoulos  3 , David J Lefer  1
Affiliations

Hydrogen Sulfide Modulates Endothelial-Mesenchymal Transition in Heart Failure

Zhen Li et al. Circ Res. .

Abstract

Background: Hydrogen sulfide is a critical endogenous signaling molecule that exerts protective effects in the setting of heart failure. Cystathionine γ-lyase (CSE), 1 of 3 hydrogen-sulfide-producing enzyme, is predominantly localized in the vascular endothelium. The interaction between the endothelial CSE-hydrogen sulfide axis and endothelial-mesenchymal transition, an important pathological process contributing to the formation of fibrosis, has yet to be investigated.

Methods: Endothelial-cell-specific CSE knockout and Endothelial cell-CSE overexpressing mice were subjected to transverse aortic constriction to induce heart failure with reduced ejection fraction. Cardiac function, vascular reactivity, and treadmill exercise capacity were measured to determine the severity of heart failure. Histological and gene expression analyses were performed to investigate changes in cardiac fibrosis and the activation of endothelial-mesenchymal transition.

Results: Endothelial-cell-specific CSE knockout mice exhibited increased endothelial-mesenchymal transition and reduced nitric oxide bioavailability in the myocardium, which was associated with increased cardiac fibrosis, impaired cardiac and vascular function, and worsened exercise performance. In contrast, genetic overexpression of CSE in endothelial cells led to increased myocardial nitric oxide, decreased endothelial-mesenchymal transition and cardiac fibrosis, preserved cardiac and endothelial function, and improved exercise capacity.

Conclusions: Our data demonstrate that endothelial CSE modulates endothelial-mesenchymal transition and ameliorate the severity of pressure-overload-induced heart failure, in part, through nitric oxide-related mechanisms. These data further suggest that endothelium-derived hydrogen sulfide is a potential therapeutic for the treatment of heart failure with reduced ejection fraction.

Keywords: endothelial cell; fibrosis; heart failure; hydrogen sulfide.

PubMed Disclaimer

Figures

Figure 1:
Figure 1:. Study Timeline.
Echocardiography was performed prior to the induction of HFrEF by TAC procedure then once every 3 weeks for a duration of 21 weeks. Invasive hemodynamic, vascular reactivity, exercise capacity, cardiac fibrosis, EndoMT activation, and other molecular determination were performed at 21 weeks post TAC. A separate set of mice were sacrificed at 6 weeks post TAC to assess early stage EndoMT activation.
Figure 2:
Figure 2:. Exacerbated pressure overload HFrEF in EC-CSE KO mice.
(A) LV posterior wall thickness, (B) LV end-diastolic diameters and (C) LV ejection fraction throughout the 21 weeks study for EC-CSE KO and control mice. (D) LV end-diastolic pressure, (E) LV relaxation constant Tau, (F) Circulating BNP, (G) aortic vascular reactivity to ACh, (H) aortic vascular reactivity to SNP, and (I) Treadmill running distance in EC-CSE KO and control mice at 21 weeks post TAC. Circled number inside bars indicates samples size. Data in (A) - (C) and (G) - (H) are analyzed with 2-way ANOVA; other data are analyzed with unpaired student t-test. Data are presented as mean ± SD.
Figure 3:
Figure 3:. Increased cardiac fibrosis in EC-CSE KO mice at 21 weeks post TAC.
Best illustrative microphotography of (A) cardiac fibrosis in interstitial area and (B) perivascular area. Total fibrosis (C) and perivascular fibrosis (D) quantified. (E) Relative fold changes in cardiac mRNA levels of a panel of fibrosis-related genes in EC-CSE KO and control mice. Circled number inside bars indicates samples size. Data are analyzed with unpaired student t-test and presented as mean ± SD. Scale bar indicates 50 μm.
Figure 4:
Figure 4:. Overactivation of EndoMT in EC-CSE KO mice.
(A) Best illustrative microphotography of heart sections stained for Vimentin (Red), VWF (green), and Dapi (blue). Vimentin+/VWF+ double positive cells displayed yellow color and quantified in (B). Relative fold changes in cardiac mRNA levels of a panel of EndoMT-related genes at 6 weeks post TAC (C) and 21 weeks post TAC (D) in EC-CSE KO and control mice. Circled number inside bars indicates samples size. Data are analyzed with unpaired student t-test and presented as mean ± SD. Scale bar indicates 50 μm.
Figure 5:
Figure 5:. Attenuated severity of pressure overload HFrEF in EC-CSE Tg mice.
(A) LV posterior wall thickness at diastole, (B) LV end-diastolic diameters, and (C) LV ejection fraction throughout the 21 weeks study for constitutive EC-CSE Tg, 10-week-delayed EC-CSE Tg, and control mice. (D) LV end-diastolic pressure, (E) LV relaxation constant Tau (F) Circulating BNP, (G) aortic vascular reactivity to ACh (H) aortic vascular reactivity to SNP, and (I) Treadmill running distance for constitutive EC-CSE Tg, 10-week-delayed EC-CSE Tg, and control mice at 21 weeks post TAC. Circled number inside bars indicates samples size. Data in (A) - (C) and (G) - (H) are analyzed with 2-way ANOVA; other data are analyzed with one-way ANOVA. Data are presented as mean ± SD.
Figure 6:
Figure 6:. Reduced cardiac fibrosis in EC-CSE Tg mice at 21 weeks post TAC.
Best illustrative microphotography of (A) cardiac fibrosis in interstitial area and (B) perivascular area; Total fibrosis (C) and perivascular fibrosis (D) quantified; (E) Relative fold changes in cardiac mRNA levels of a panel of fibrosis-related genes for constitutive EC-CSE Tg, 10-week-delayed EC-CSE Tg, and control mice. Circled number inside bars indicates samples size. Data are analyzed with one-way ANOVA and presented as mean ± SD. Scale bar indicates 50 μm.
Figure 7:
Figure 7:. Downregulation of EndoMT in EC-CSE Tg mice.
(A) Best illustrative microphotography of heart sections stained for Vimentin (Red), VWF (green), and Dapi (blue); Vimentin+/VWF+ double positive cells displayed yellow color and quantified in (B); Relative fold changes in cardiac mRNA levels of a panel of EndoMT-related genes at 6 weeks post TAC (C) and 21 weeks post TAC (D) for constitutive EC-CSE Tg, 10-week-delayed EC-CSE Tg, and control mice. Circled number inside bars indicates samples size. Data are analyzed with one-way ANOVA and presented as mean ± SD. Scale bar indicates 50 μm.
See this image and copyright information in PMC

References

    1. Bozkurt B, Hershberger RE, Butler J, Grady KL, Heidenreich PA, Isler ML, Kirklin JK and Weintraub WS. 2021 ACC/AHA Key Data Elements and Definitions for Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Clinical Data Standards for Heart Failure). Circ Cardiovasc Qual Outcomes. 2021:HCQ0000000000000102. - PMC - PubMed
    1. Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Cheng S, Delling FN, Elkind MSV, Evenson KR, Ferguson JF, Gupta DK, Khan SS, Kissela BM, Knutson KL, Lee CD, Lewis TT, Liu J, Loop MS, Lutsey PL, Ma J, Mackey J, Martin SS, Matchar DB, Mussolino ME, Navaneethan SD, Perak AM, Roth GA, Samad Z, Satou GM, Schroeder EB, Shah SH, Shay CM, Stokes A, VanWagner LB, Wang NY, Tsao CW, American Heart Association Council on E, Prevention Statistics C and Stroke Statistics S. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation. 2021;143:e254–e743. - PubMed
    1. Nabel EG and Braunwald E. A tale of coronary artery disease and myocardial infarction. N Engl J Med. 2012;366:54–63. - PubMed
    1. Heidenreich PA, Albert NM, Allen LA, Bluemke DA, Butler J, Fonarow GC, Ikonomidis JS, Khavjou O, Konstam MA, Maddox TM, Nichol G, Pham M, Pina IL, Trogdon JG, American Heart Association Advocacy Coordinating C, Council on Arteriosclerosis T, Vascular B, Council on Cardiovascular R, Intervention, Council on Clinical C, Council on E, Prevention and Stroke C. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6:606–19. - PMC - PubMed
    1. Alem MM. Endothelial Dysfunction in Chronic Heart Failure: Assessment, Findings, Significance, and Potential Therapeutic Targets. Int J Mol Sci. 2019;20. - PMC - PubMed

Publication types