Circulating levels of angiotensinogen, sex and hormone therapy - the multi-ethnic study of atherosclerosis (mesa)

Background: Angiotensinogen, the unique precursor of all angiotensin hormones of the Renin-Angiotensin-Aldosterone System (RAAS), is now a potential target in a novel pharmacological approach to hypertension. Investigating the factors that influence angiotensinogen levels, including sex hormones, may have important therapeutic implications. Methods: Plasma angiotensinogen and sex hormones levels were measured in 5,171 Multi-Ethnic Study of Atherosclerosis (MESA) participants. Linear models were employed to determine the associations of angiotensinogen with sex hormones, and mediation analysis was performed to evaluate the effect of HT on blood pressure (BP) and hypertension through angiotensinogen. Results: Angiotensinogen levels were significantly higher in postmenopausal women receiving HT (n=760) compared to women not receiving HRT (n=1,675) and in men (n=2,736). A positive association was present between angiotensinogen and estrogen levels that differed in magnitude between sexes and by HT status among postmenopausal women (women on HT: r=0.44, p< 0.0001; women not on HT: r=0.09, p=0.0002; and men: r= 0.07, p=0.0003). The type of HT formulation (estrogen or estrogen/progesterone) and its duration of use did not significantly affect angiotensinogen levels. HT indirectly increased systolic BP (β=1.24) and the odds of hypertension (OR=1.065) through its effect of increasing angiotensinogen. Conclusions: A positive association was present between angiotensinogen and estrogen levels that differed by HT status. HT impacts systolic BP and hypertension indirectly by increasing angiotensinogen. This study underscores the role of angiotensinogen in hypertension, and the complex relationship between HT and hypertension. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was supported by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences (NIGMS) of the National Institutes of Health under grant number P20GM103451 and a Research Enhancement Award to PT from NIGMS under grant number SC1GM139730. Additional support for this research, including sample processing and angiotensinogen measurements was provided by Ionis Pharmaceuticals, Inc. This research was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168 and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. This paper has been reviewed and approved by the MESA Publications and Presentations Committee. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was approved by the institutional review boards of the participating institutions, and all participants gave written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Interested investigators may request access to the data by contacting the MESA data coordinating center (chsccweb@u.washington.edu).