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Cardiac epigenetic changes in VEGF signaling genes associate with myocardial microvascular rarefaction in experimental chronic kidney disease

Commented by ESC Working Group on Coronary Pathophysiology & Microcirculation



Chronic kidney disease, epigenetic changes and coronary microvascular disease

Dr. Richard Bright noted, as early as 1836, that individuals with albuminous urine had enlarged hearts. 1 Since then, it has been demonstrated that left ventricular hypertrophy is related to both mild and end-stage chronic kidney disease (CKD). Although cardiac hypertrophy in CKD patients is typically attributed to hypertension, circulating uremic toxins and systemic inflammation may also have a direct effect on the heart, resulting in oxidative stress, loss of NO, vascular endothelial dysfunction and impaired left ventricular relaxation. Indeed, worsening renal function is strongly associated with coronary microvascular dysfunction (CMD).2-4 Importantly, both impaired left ventricular relaxation and CMD are risk factors for development of heart failure with preserved ejection fraction (HFpEF). Furthermore, within the heterogeneous group of HFpEF patients, patients with systemic inflammation and CKD have the highest risk of hospitalization,5 suggesting that CKD is also a risk factor for worsening of cardiac function.

Given the large similarities between swine and humans, and to further elucidate the mechanistic link between CKD, CMD and HFpEF, several groups have developed swine models of renovascular disease, using DOCA salt,6 renal micro-embolization7 or renal artery stenosis8, 9 in absence and presence of metabolic derangement and confirmed the presence of left ventricular diastolic dysfunction and impaired relaxation. In these models, CKD and metabolic derangement acted synergistically in their detrimental effect on the heart. In depth characterization of myocardial structure and function showed that cardiomyocyte stiffening, mediated by altered titin expression or phosphorylation,6, 7 and increased interstitial fibrosis7, 9 contributed to the increased myocardial stiffness.

In order to further elucidate a mechanistic link between CKD and the myocardial tissue changes, Chade and Eirin performed unbiased molecular analyses of the myocardial tissue of swine with renovascular hypertension with metabolic derangement.10, 11 In their first study, they identified up- and down regulated pathways, by associating changes in miRNAs with alterations in the transcriptomic profile. Differentially regulated pathways included pathways involved in ATP synthesis, hypertrophic cardiomyopathy and extracellular matrix remodeling.10 Intriguingly, they also found ‘regulation of transcription’ to be differentially regulated. In a follow-up study, they therefore investigated epigenetic changes, specifically methylation of the carbon-5 of cytosine (5mC) using methylated DNA immuno-precipitation combined with deep sequencing (MeDIP-seq), in the myocardium of these swine.11 Biological pathway analysis showed that the genes found to be hypermethylated were predominantly involved in promoting VEGF- and VEGF-related signaling. The methylation data, implying impaired VEGF signaling, were confirmed by showing that mRNA encoding VEGFA, the VEGF receptor KDR, as well as VEGF-related genes eNOS and AKT1 was lower in the myocardium of animals with CKD. Altogether this resulted in lower VEGF protein levels. These findings suggest impaired angiogenesis, which was supported by post-mortem micro-CT data showing lower microvascular density in pigs with renovascular hypertension and metabolic derangement 11 and are consistent with previous studies showing microvascular dysfunction with a loss of nitric oxide12 and reduced capillary density in animal models with CKD. 7, 9 
Another pathway shown to be changed in both studies of Eirin and Chade is the epidermal growth factor (EGF) signaling pathway, which signals through the EGF-receptor also known as ErbB. ERB signalling genes were found to be hypomethylated, indicating that ERB signaling is activated. ERB-signaling is thought to play a dual role in the cardiovascular system, as it may elicit beneficial as well as detrimental effects. Indeed, ERB-signaling is directly activated by peptides of the Renin-Angiotensin-Aldosterone system (RAAS) such as Ang II,13 providing a mechanism for its activation in CKD. In animal models of cardiac injury induced by diabetes or Ang II infusion, ERB-signaling promotes oxidative stress, fibrosis and hypertrophy.14 On the other hand, ERB signaling maintains basic cellular function for physiological development and functioning of the heart and vasculature. Here, its activation appears to be primarily mediated through neuregulin-1. Neuregulin mediated ERB signaling has been shown to promote cardiac repair and induce angiogenesis;13 suggesting that hypomethylation of ERB signaling genes may have been a counterregulatory mechanism for disruption of VEGF signaling. 

The studies by Eirin and Chade,11, 15 underscore the value of large animal models to assess long-term effects of dysfunction of one organ (i.e. the kidney), on another (i.e. the heart). Well-characterized large animal models enable ex-vivo measurements allowing the combination of transcriptomic and epigenetic data with myocardial histology and three-dimensional vascular density measurements. They show conclusively that CKD impacts expression of angiogenic genes through changes in methylation, thereby providing another novel mechanism through which CKD impacts the coronary microvasculature and cardiac remodeling.

References


1.         Bright R. Tabular view of the morbid appearances in 100 cases connected with albuminous urine.  Cases and Observations illustrative of renal disease accompanied with teh secretion of albuminous urine. Guy’s hospital records, 1836:44-64.

2.         Charytan DM, Skali H, Shah NR, Veeranna V, Cheezum MK, Taqueti VR, Kato T, Bibbo CR, Hainer J, Dorbala S, Blankstein R, Di Carli MF. Coronary flow reserve is predictive of the risk of cardiovascular death regardless of chronic kidney disease stage. Kidney Int 2018;93:501-509.

3.         Jain V, Gupta K, Bhatia K, Rajapreyar I, Singh A, Zhou W, Klein A, Nanda NC, Prabhu SD, Bajaj NS. Coronary flow abnormalities in chronic kidney disease: A systematic review and meta-analysis. Echocardiography 2022;39:1382-1390.

4.         Mohandas R, Segal MS, Huo T, Handberg EM, Petersen JW, Johnson BD, Sopko G, Bairey Merz CN, Pepine CJ. Renal function and coronary microvascular dysfunction in women with symptoms/signs of ischemia. PLoS One 2015;10:e0125374.

5.         Woolley RJ, Ceelen D, Ouwerkerk W, Tromp J, Figarska SM, Anker SD, Dickstein K, Filippatos G, Zannad F, Metra M, Ng L, Samani N, van Veldhuisen DJ, Lang C, Lam CS, Voors AA. Machine learning based on biomarker profiles identifies distinct subgroups of heart failure with preserved ejection fraction. Eur J Heart Fail 2021;23:983-991.

6.         Schwarzl M, Hamdani N, Seiler S, Alogna A, Manninger M, Reilly S, Zirngast B, Kirsch A, Steendijk P, Verderber J, Zweiker D, Eller P, Hofler G, Schauer S, Eller K, Maechler H, Pieske BM, Linke WA, Casadei B, Post H. A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction. Am J Physiol Heart Circ Physiol 2015;309:H1407-1418.

7.         Sorop O, Heinonen I, van Kranenburg M, van de Wouw J, de Beer VJ, Nguyen ITN, Octavia Y, van Duin RWB, Stam K, van Geuns RJ, Wielopolski PA, Krestin GP, van den Meiracker AH, Verjans R, van Bilsen M, Danser AHJ, Paulus WJ, Cheng C, Linke WA, Joles JA, Verhaar MC, van der Velden J, Merkus D, Duncker DJ. Multiple common comorbidities produce left ventricular diastolic dysfunction associated with coronary microvascular dysfunction, oxidative stress, and myocardial stiffening. Cardiovasc Res 2018;114:954-964.

8.         Chade AR, Engel JE, Hall ME, Eirin A, Bidwell GL, 3rd. Intrarenal modulation of NF-kappaB activity attenuates cardiac injury in a swine model of CKD: a renal-cardio axis. Am J Physiol Renal Physiol 2021;321:F411-F423.

9.         Yu S, Jiang K, Zhu XY, Ferguson CM, Krier JD, Lerman A, Lerman LO. Endovascular reversal of renovascular hypertension blunts cardiac dysfunction and deformation in swine. J Hypertens 2021;39:556-562.

10.       Chade AR, Eirin A. Cardiac micro-RNA and transcriptomic profile of a novel swine model of chronic kidney disease and left ventricular diastolic dysfunction. Am J Physiol Heart Circ Physiol 2022;323:H659-H669.

11.       Eirin A, Chade AR. Cardiac epigenetic changes in VEGF signaling genes associate with myocardial microvascular rarefaction in experimental chronic kidney disease. Am J Physiol Heart Circ Physiol 2023;324:H14-H25.

12.       van de Wouw J, Sorop O, van Drie RWA, Joles JA, Danser AHJ, Verhaar MC, Merkus D, Duncker DJ. Reduced nitric oxide bioavailability impairs myocardial oxygen balance during exercise in swine with multiple risk factors. Basic Res Cardiol 2021;116:50.

13.       Wang Y, Wei J, Zhang P, Zhang X, Wang Y, Chen W, Zhao Y, Cui X. Neuregulin-1, a potential therapeutic target for cardiac repair. Front Pharmacol 2022;13:945206.

14.       Shraim BA, Moursi MO, Benter IF, Habib AM, Akhtar S. The Role of Epidermal Growth Factor Receptor Family of Receptor Tyrosine Kinases in Mediating Diabetes-Induced Cardiovascular Complications. Front Pharmacol 2021;12:701390.

15.       Eirin A, Chade AR. Cardiac epigenetic changes in VEGF signaling genes associates with myocardial microvascular rarefaction in experimental chronic kidney disease. Am J Physiol Heart Circ Physiol 2022.

16.       Nargesi AA, Farah MC, Zhu XY, Zhang L, Tang H, Jordan KL, Saadiq IM, Lerman A, Lerman LO, Eirin A. Renovascular Hypertension Induces Myocardial Mitochondrial Damage, Contributing to Cardiac Injury and Dysfunction in Pigs With Metabolic Syndrome. Am J Hypertens 2021;34:172-182.

17.       Farahani RA, Yu S, Ferguson CM, Zhu XY, Tang H, Jordan KL, Saadiq IM, Herrmann SM, Chade AR, Lerman A, Lerman LO, Eirin A. Renal Revascularization Attenuates Myocardial Mitochondrial Damage and Improves Diastolic Function in Pigs with Metabolic Syndrome and Renovascular Hypertension. J Cardiovasc Transl Res 2022;15:15-26.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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