Prolylcarboxypeptidase Alleviates Hypertensive Cardiac Remodeling by Regulating Myocardial Tissue Angiotensin II.

Background Prolonged activation of angiotensin II is the main mediator that contributes to the development of heart diseases, so converting angiotensin II into angiotensin 1-7 has emerged as a new strategy to attenuate detrimental effects of angiotensin II. Prolylcarboxypeptidase is a lysosomal pro-X carboxypeptidase that is able to cleave angiotensin II at a preferential acidic pH optimum. However, insufficient attention has been given to the cardioprotective functions of prolylcarboxylpeptidase. Methods and Results We established a CRISPR/CRISPR-associated protein 9-mediated global prolylcarboxylpeptidase-knockout and adeno-associated virus serotype 9-mediated cardiac prolylcarboxylpeptidase overexpression mouse models, which were challenged with the angiotensin II infusion (2 mg/kg per day) for 4 weeks, aiming to investigate the cardioprotective effect of prolylcarboxylpeptidase against hypertensive cardiac hypertrophy. Prolylcarboxylpeptidase expression was upregulated after 2 weeks of angiotensin II infusion and then became downregulated afterward in wild-type mouse myocardium, suggesting its compensatory function against angiotensin II stress. Moreover, angiotensin II-treated prolylcarboxylpeptidase-knockout mice showed aggravated cardiac remodeling and dampened cardiac contractility independent of hypertension. We also found that prolylcarboxylpeptidase localizes in cardiomyocyte lysosomes, and loss of prolylcarboxylpeptidase led to excessive angiotensin II levels in myocardial tissue. Further screening demonstrated that hypertrophic prolylcarboxylpeptidase-knockout hearts showed upregulated extracellular signal-regulated kinases 1/2 and downregulated protein kinase B activities. Importantly, adeno-associated virus serotype 9-mediated restoration of prolylcarboxylpeptidase expression in prolylcarboxylpeptidase-knockout hearts alleviated angiotensin II-induced hypertrophy, fibrosis, and cell death. Interestingly, the combination of adeno-associated virus serotype 9-mediated prolylcarboxylpeptidase overexpression and an antihypertensive drug, losartan, likely conferred more effective protection than a single treatment protocol to mitigate angiotensin II-induced cardiac dysfunction. Conclusions Our data demonstrate that prolylcarboxylpeptidase protects the heart from angiotensin II-induced hypertrophic remodeling by controlling myocardial angiotensin II levels.

Systemic lupus erythematosus in the setting of HIV-1 infection: a longitudinal analysis.

Patients with concomitant HIV-1 infection and systemic lupus erythematosus (SLE) followed longitudinally at an HIV outpatient clinic from 1994 to 2019 were examined. Patients met 1982 and 1997 ACR classification criteria for SLE at the Thomas Street clinic from 1994 to 2019. Clinical and demographic comparisons were made with a non HIV-SLE patient cohort, the Lupus in Minorities Studies, Nature versus Nurture (LUMINA) study. Twenty-two patients with concomitant HIV-1 infection and SLE were identified, including 18 females, 3 males, and 1 male to female transgender. Overall, 81.8% of SLE-HIV patients were African-American compared to 55.3% of the 5856 patients seen at the HIV clinic from 2016 to 2017 (p = 0.02, OR = 3.6). There were 12 patients that developed HIV-1 in the setting of SLE and 10 patients that developed SLE in the setting HIV-1. This demographic distribution was significant when compared with the 1604 unique patients in the HIV rheumatology clinic from 1994 to 2019 (p = 0.03, OR = 5.9) and also significant when compared with the 5856 patients attending the county HIV clinic overall in 2016-2017 (p = 0.008, OR = 7.2). When comparing with the non-HIV SLE cohort, anti-dsDNA antibodies were noted less frequently in all HIV-SLE patients (p = 0.0002) including all sub-cohorts of our patients. Skin/mucosal involvement (p = 0.0003) and cytopenias (p = 0.0001) occurred less frequently in the patients that were diagnosed with HIV after their SLE diagnosis compared to non-HIV SLE patients. In a large county HIV clinic setting, the prevalence of SLE was significantly higher in African American women. Anti-dsDNA antibodies were less frequent in HIV-1 positive SLE patients.Key Points• This paper presents clinical and laboratory data on the largest cohort of SLE patients with HIV-1 infection reported to date.• The prevalence of SLE in a large outpatient HIV-1 clinic was larger than reported in HIV negative population studies.• The prevalence of SLE was particularly high in black HIV-1 infected women.• Skin/mucosal involvement and anti-ds DNA antibodies were less common in patients with HIV-1 and SLE compared to patients with SLE without SLE>.

Rheumatic manifestations associated with HIV in the highly active antiretroviral therapy era.

PURPOSE OF REVIEW: To evaluate the rheumatic manifestations associated with HIV infection in the highly active antiretroviral therapy (HAART) era. RECENT FINDINGS: The overall prevalence of rheumatic manifestations in HIV population is approximately 9% with various clinical features. Anti-TNF agents do not appear to adversely affect the CD4 cell counts or viral load if the HIV infection is well controlled prior to initiation of therapy. SUMMARY: In the HAART era, HIV-infected individuals can be affected by various rheumatic syndromes including arthritis, spondyloarthritis, DILS, vasculitides, connective tissue disease, myopathies, and musculoskeletal diseases. With the use of HAART, the prevalence of spondyloarthritis and Diffuse Infiltrative Lymphocytosis Syndrome has decreased, whereas the musculoskeletal complications of HIV and HAART, such as osteopenia, osteonecrosis, and infection continue to be a concern. With immune restoration, various inflammatory and autoimmune diseases, such as SLE, rheumatoid arthritis, and polymyositis may occur de novo or exacerbate. Most antirheumatic therapies used in HIV-negative individuals appear to be safe and effective in the setting of HIV infection as long as prudent guidelines are followed.