The prorenin/renin receptor ((P)RR) is a multifunctional protein that is widely distributed in various organs. Despite intensive research for more than 20 years, this receptor has not been fully characterized. In this study, we generated mice overexpressing the tubular epithelial (P)RR gene ((P)RR-TG mice) to test the previously reported functional role of (P)RR by Ramkumar et al. in 2015 using tubular specific (P)RR KO mice. (P)RR-TG mice were maintained and analyzed in individual metabolic cages and were administered angiotensin II blocker (ARB), direct renin inhibitor (DRI), and bafilomycin, that is, vacuolar ATPase (V-ATPase) antagonist. (P)RR-TG mice were hypertensive and had alkalized urine with lower osmolality and Na⁺ excretion. ARB and DRI, but not bafilomycin, concurrently decreased blood pressure. Bafilomycin acidized urine of (P)RR-TG mice, or equivalently this phenomenon restored the effect of overexpressed transgene, suggesting that (P)RR functioned as a V-ATPase in renal tubules. Afterall, (P)RR-TG mice were mated with alternative renin transgenic mice (ARen2-TG), which we identified as intracellular renin previously, to generate double transgenic mice (DT-TG). Lethal renal tubular damage was observed in DT-TG mice, suggesting that intracellular renin may be a ligand for (P)RR in tubules. In summary, (P)RR did not substantially affect the tissue renin-angiotensin system (RAS) in our model of tubular specific (P)RR gene over-expression, but alternative intracellular renin may be involved in (P)RR signaling in addition to conventional V-ATPase function. Further investigations are warranted.

To explore the biological and immunological basis of human rheumatoid arthritis and human atherosclerosis, we planned and reported a detailed design and rationale for Orencia Atherosclerosis and Rheumatoid Arthritis Study (ORACLE Arthritis Study) using highly sensitive, high-throughput, human autoantibody measurement methods with cell-free protein synthesis technologies. Our previous study revealed that subjects with atherosclerosis had various autoantibodies in their sera, and the titers of anti-Th2 cytokine antibodies were correlated with the severity of atherosclerosis. Because rheumatoid arthritis is a representative autoimmune disease, we hypothesized that both rheumatoid arthritis and atherosclerosis are commonly developed by autoantibody-mediated autoimmune processes, leading to incessant inflammatory changes in both articular joint tissues and vessel walls. We planned a detailed examination involving carotid artery ultrasonography, measurements of adhesion molecules, such as ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular cell adhesion molecule 1) for the evaluation of atherosclerosis progression, and high-throughput, high-sensitivity, autoantibody analyses using cell-free technologies, with detailed examinations of the disease activity of rheumatoid arthritis. Analyses of correlations and associations between biological markers and degrees of carotid atherosclerosis over time under consistent conditions may enable us to understand the biological and humoral immunity background of human atherosclerosis and autoimmune diseases.

Background: Cardiovascular diseases (CVDs) remain a leading cause of morbidity and mortality, despite advances in treatment. Early detection of vascular aging is critical, as preclinical atherosclerosis often remains undiagnosed. AI-determined vascular age, originally developed using carotid-femoral pulse wave velocity (cf-PWV), may help to identify individuals at elevated risk. This study aimed to evaluate the clinical utility of an alternative AI-determined vascular age model based on the arterial velocity pulse index (AVI) and arterial pressure volume index (API) in a Japanese hospital-based cohort. Methods: This retrospective, exploratory study analyzed electronic health records of 408 patients from Yokohama City University Hospital. This study was approved by the Clinical Research Ethics Committee (approval numbers: B180300040, F240500007), and patient consent was obtained through an opt-out process. AI-determined vascular age was estimated using a Generalized Additive Model (GAM) with backward stepwise regression, substituting cf-PWV with AVI and API. Correlations with chronological age were assessed, and comparisons of cardiovascular and renal function markers were performed across age-stratified groups. Results: AI-determined vascular age showed a strong correlation with chronological age (p < 0.05). Significant differences were observed in cardiac diastolic function parameters, B-type natriuretic peptide (BNP), and estimated glomerular filtration rate (eGFR) between the highest and lowest quintiles of AI-determined vascular age. Conclusions: AI-determined vascular age using AVI and API appears to be a feasible surrogate for cf-PWV in clinical settings. This index may aid in stratifying vascular aging and identifying individuals who could benefit from early cardiovascular risk management.

Background: Recently, the arterial velocity pulse index (AVI) and arterial pressure volume index (API) have been used to evaluate arterial stiffness and endothelial function. As arterial stiffness and endothelial injury are risk factors for coronary artery disease (CAD), these two indexes are therefore expected to predict and evaluate the future risk of CAD and cardiovascular events before clinical manifestations. Methods: A total of 90 consecutive patients with coronary angiography (CAG) were enrolled. After excluding normal patients and acute coronary syndrome patients, forty-seven patients with CAD and thirty-two patients with coronary atherosclerosis, and baseline characteristics data were collected. A multifunctional blood pressure monitoring device, AVE-1500 (Shisei Datum, Tokyo, Japan), was used to measure the AVI and API before CAG, and immediately and 2 h, 24 h, and 48 h after CAG and (or) PCI in all the selected participants. Results: After adjusting for various variables using stepwise multiple linear regression analyses, we found that the AVI in the CAD subjects was significantly higher than that in the coronary atherosclerosis subjects before CAG (p = 0.02), immediately after CAG/PCI (p = 0.01), and 48 h after CAG/PCI (p = 0.01), whereas the AVI decreased 24–48 h rather than immediately after CAG/PCI in the CAD group. Moreover, we also found that the API clearly changed in both groups during the periprocedural period of CAG (p = 0.01). Conclusions: In accordance with the results, we propose that the API and AVI may be useful for predicting the early stage of CAD and may be promising as indicators to assess the effect of early revascularization.

Background: The Arterial Velocity Pulse Index (AVI) and Arterial Pressure–Volume Index (API) are novel non-invasive indices of arterial stiffness derived from cuff-oscillometric measurements. Previous studies have shown that elevated AVI and API are associated with the severity of coronary artery disease and the ability to predict future cardiovascular events. However, the hemodynamic and echocardiographic characteristics of patients with concomitantly high AVI and API remain unclear. Methods: We retrospectively analyzed 112 consecutive cardiovascular outpatients (mean age 69.1 ± 12.2 years, 64.3% male) seen between January and April 2019 at Yokohama City University Hospital. The AVI and API were measured using a multifunctional sphygmomanometer (PASESA AVE1500, Shisei Datum, Japan) and averaged over a maximum of three measurements. Patients were classified into four groups according to previously established cutoff values (AVI ≥ 27, API ≥ 32). Central arterial pulse wave parameters were assessed using SphygmoCor XCEL (AtCor Medical, Sydney, Australia), and echocardiographic parameters were obtained according to standard protocols. Intergroup differences were analyzed using the Kruskal–Wallis test with Steel–Dwass post hoc comparisons. Results: Compared with the low-risk group (low AVI/low API), the high-risk group (high AVI/high API) had significantly higher brachial systolic BP (139.2 [132.8–149] vs. 128 [120–136.7] mmHg, p = 0.0011), central systolic BP (127.5 [122.3–139] vs. 117.7 [110.3–123.7] mmHg, p = 0.0018), and central pulse pressure (56.2 [51.4–60.3] vs. 37.7 [32–43] mmHg, p < 0.001). The forward and reflected wave amplitudes were significantly greater, with prolonged ejection duration and aortic T2 time. The Buckberg subendocardial viability ratio was significantly lower in the high-risk group (129.5 [119.7–145.2] vs. 148.3 [130–168.3], p = 0.040). Echocardiography revealed reduced e′ velocity (5 [4.1–5.8] vs. 6.7 [5.2–8] cm/s, p = 0.035) and increased E/e′ (13.2 [11.1–15.1] vs. 9.7 [7.9–11.3], p = 0.026) in the high-risk group, suggesting the presence of impaired diastolic function without reduced LVEF. Conclusions: Patients with high AVI and API exhibited greater central and peripheral arterial stiffness, higher systolic and pulse pressures, and impaired diastolic function compared with those with low values. These findings support the use of a cardiovascular pathophysiological model in which elevated AVI/API identify individuals at increased risk of progression to heart failure and ischemic heart disease.