Inhibition of Histone 3 Lysine 4 Histone Methyltransferase Attenuates DOCA-Salt-Induced Hypertension

Abstract

Emerging evidence suggests that epigenetic regulatory mechanisms contribute to the development of hypertension. However, whether there is significance of epigenetics on neurogenic hypertension development is not fully understood. We previously reported an elevation of Histone 3 Lysine 4 (H3K4) trimethylation in the paraventricular nucleus of the hypothalamus (PVN). Accordingly, we hypothesize that H3K4 histone methyltransferase (HMT) in the PVN contributes to the development of DOCA-salt hypertension. To test our hypothesis, C57Bl/6J mice were implanted with SHAM or DOCA (50mg) pellets and given free access to water or saline (0.9% NaCl) respectively for 3, 7, or 21 days. H3K4 HMT activity were assessed in the PVN (n = 3-5 mice/group) and expressed as fold change. The HMT activity in the PVN was increased as early as 3 days after DOCA-salt compared with SHAM (6.1 ± 0.69 vs. 1.0 ± 0.73, P < 0.05), remained elevated at day 7 (6.3 ± 1.29 vs. 1.0 ± 0.90, P < 0.05) and day 21 (1.6 ± 0.07 vs. 1.0 ± 0.07, P < 0.05) of DOCA-salt treatment compared with SHAM. To examine the contribution of HMT activity to the development of DOCA-Salt hypertension, another cohort of mice (n = 3-5 mice/group) were implanted with telemetry transmitters to mornitor the blood pressure. After 10 days of recovery, mice treated with DOCA-Salt salt and intracerebroventricularly (ICV) infused with either artificial CSF or 5'-methylthioadenosine (MTA), a H3K4 HMT inhibitor, for 21 days. Importantly, ICV infusion of MTA attenuated mean arterial pressure (123.1 ± 6.3 vs. 138.5 ± 7.4 mmHg, P<0.05) compared with the control following DOCA-salt treatment. In addition, ICV infusion of MTA significantly reduced the H3K4 HMT activity (1.0 ± 0.08 vs 1.7 ± 0.07, P < 0.05) compared with aCSF group following 21 days of DOCA-salt treatment confirming the effectiveness of the inhibitor. In summary, these findings suggest the importance of elevated HMT activity in the PVN in DOCA-salt-induced hypertension. Further studies will be performed to identify the downstream targets of HMT and the mechanisms involved. R01HL122770, 1P20GM130459, R35HL155008-01S1 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.