Rosiglitazone, a Ligand to PPAR<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mrow><mml:mi>γ</mml:mi></mml:mrow></mml:math>, Improves Blood Pressure and Vascular Function through Renin-Angiotensin System Regulation

Sánchez-Aguilar, María; Ibarra-Lara, Luz; Valle-Mondragón, Leonardo Del; Rubio-Ruiz, María Esther; Aguilar-Navarro, Alicia G.; Zamorano-Carrillo, Absalom; Ramírez-Ortega, Margarita; Pastelín-Hernández, Gustavo; Sánchez-Mendoza, Alicia

doi:10.1155/2019/1371758

Cited by 26 publications

(26 citation statements)

References 44 publications

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“…17 Preclinical data support the hypothesis that long-term intake of ACE inhibitors, ARBs, statins, corticosteroids, and hypoglycemic agents may increase susceptibility to SARS-CoV-2 infection by favoring viral replication owing to upregulation of ACE2 receptors. [27][28][29][30][31] On the other hand, in patients with COVID-19, these same drugs may theoretically improve the clinical course by rebalancing the dysregulated renin-angiotensin system and thus reducing vasoconstriction, inflammation, and oxidation. In a recent large case series, mortality of patients with hypertension taking ACE inhibitors or ARBs was higher than that of patients with hypertension not taking these drugs, but no statistic confirmed the association between chronic therapy with ACE inhibitors or ARBs and mortality.…”

Section: Discussionmentioning

confidence: 99%

Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy

et al. 2020

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IMPORTANCE Many patients with coronavirus disease 2019 (COVID-19) are critically ill and require care in the intensive care unit (ICU). OBJECTIVE To evaluate the independent risk factors associated with mortality of patients with COVID-19 requiring treatment in ICUs in the Lombardy region of Italy. DESIGN, SETTING, AND PARTICIPANTS This retrospective, observational cohort study included 3988 consecutive critically ill patients with laboratory-confirmed COVID-19 referred for ICU admission to the coordinating center (Fondazione IRCCS [Istituto di Ricovero e Cura a Carattere Scientifico] Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy) of the COVID-19 Lombardy ICU Network from February 20 to April 22, 2020. Infection with severe acute respiratory syndrome coronavirus 2 was confirmed by real-time reverse transcriptase-polymerase chain reaction assay of nasopharyngeal swabs. Follow-up was completed on May 30, 2020. EXPOSURES Baseline characteristics, comorbidities, long-term medications, and ventilatory support at ICU admission. MAIN OUTCOMES AND MEASURES Time to death in days from ICU admission to hospital discharge. The independent risk factors associated with mortality were evaluated with a multivariable Cox proportional hazards regression. RESULTS Of the 3988 patients included in this cohort study, the median age was 63 (interquartile range [IQR] 56-69) years; 3188 (79.9%; 95% CI, 78.7%-81.1%) were men, and 1998 of 3300 (60.5%; 95% CI, 58.9%-62.2%) had at least 1 comorbidity. At ICU admission, 2929 patients (87.3%; 95% CI, 86.1%-88.4%) required invasive mechanical ventilation (IMV). The median follow-up was 44 (95% CI, 40-47; IQR, 11-69; range, 0-100) days; median time from symptoms onset to ICU admission was 10 (95% CI, 9-10; IQR, 6-14) days; median length of ICU stay was 12 (95% CI, 12-13; IQR, 6-21) days; and median length of IMV was 10 (95% CI, 10-11; IQR, 6-17) days. Cumulative observation time was 164 305 patient-days. Hospital and ICU mortality rates were 12 (95% CI, 11-12) and 27 (95% CI, 26-29) per 1000 patients-days, respectively. In the subgroup of the first 1715 patients, as of May 30, 2020, 865 (50.4%) had been discharged from the ICU, 836 (48.7%) had died in the ICU, and 14 (0.8%) were still in the ICU; overall, 915 patients (53.4%) died in the hospital. Independent risk factors associated with mortality included older age (hazard ratio [HR], 1.75; 95% CI, 1.60-1.92), male sex (HR, 1.57; 95% CI, 1.31-1.88), high fraction of inspired oxygen (FiO 2) (HR, 1.14; 95% CI, 1.10-1.19), high positive end-expiratory pressure (HR, 1.04; 95% CI, 1.01-1.06) or low PaO 2 :FiO 2 ratio (HR, 0.80; 95% CI, 0.74-0.87) on ICU admission, and history of chronic obstructive pulmonary disease (HR, 1.68; 95% CI, 1.28-2.19), hypercholesterolemia (HR, 1.25; 95% CI, 1.02-1.52), and type 2 diabetes (HR, 1.18; 95% CI, 1.01-1.39). No medication was independently associated with mortality (angiotensin-converting enzyme inhibitors HR, 1.17; 95% CI, 0.97-1.42; angiotensin receptor blockers HR, 1.05; 95% CI, 0.85-1.29). CONCLUS...

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Section: Discussionmentioning

confidence: 99%

Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy

et al. 2020

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“…Finally, the peroxisome proliferatoractivated receptor-␥ (PPAR-␥) may influence ACE-2 expression as well. The PPAR-␥ agonist rosiglitazone increased ACE2 protein levels twofold in the aorta of hypertensive rats following aortic coarctation (39). Oudit and colleagues (61) found that telmisartan, a partial PPAR-␥ agonist, also increased ACE2 protein expression in aorta which was associated with greater PPAR-␥ content in the spontaneously hypertensive rat.…”

mentioning

confidence: 97%

“…Thus, the ACE2 peptidase pathway constitutes a key inflexion point in the processing pathway of the RAAS. Consequently, the loss of ACE2 may shift the system to an overall higher ANG II and lower Ang-(1-7) tone (4,5,39). In contrast, ACE forms ANG II and degrades Ang-(1-7), which produces the opposite processing of ACE2 and promotes an increase in blood pressure, inflammation, and fibrosis ( Fig.…”

mentioning

confidence: 99%

COVID-19, ACE2, and the cardiovascular consequences

South

Diz

Chappell

2020

American Journal of Physiology-Heart and Circulatory Physiology

692

721

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The novel SARS coronavirus SARS-CoV-2 pandemic may be particularly deleterious to patients with underlying cardiovascular disease (CVD). The mechanism for SARS-CoV-2 infection is the requisite binding of the virus to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. Recognition that ACE2 is the coreceptor for the coronavirus has prompted new therapeutic approaches to block the enzyme or reduce its expression to prevent the cellular entry and SARS-CoV-2 infection in tissues that express ACE2 including lung, heart, kidney, brain, and gut. ACE2, however, is a key enzymatic component of the renin-angiotensin-aldosterone system (RAAS); ACE2 degrades ANG II, a peptide with multiple actions that promote CVD, and generates Ang-(1-7), which antagonizes the effects of ANG II. Moreover, experimental evidence suggests that RAAS blockade by ACE inhibitors, ANG II type 1 receptor antagonists, and mineralocorticoid antagonists, as well as statins, enhance ACE2 which, in part, contributes to the benefit of these regimens. In lieu of the fact that many older patients with hypertension or other CVDs are routinely treated with RAAS blockers and statins, new clinical concerns have developed regarding whether these patients are at greater risk for SARS-CoV-2 infection, whether RAAS and statin therapy should be discontinued, and the potential consequences of RAAS blockade to COVID-19-related pathologies such as acute and chronic respiratory disease. The current perspective critically examines the evidence for ACE2 regulation by RAAS blockade and statins, the cardiovascular benefits of ACE2, and whether ACE2 blockade is a viable approach to attenuate COVID-19.

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“…Of note, Ang II circulatory levels correlated well with viral load and negative cardio-respiratory function in the SARS-CoV-2 patient cohort [41]. The role of PARP in the modulation of ACE2 was also implicated in hypertensive rats, where inhibition of PARP could enrich ACE2 protein levels [153]. These data could explain the high prevalence (15-40%) of hypertension in COVID-19 patients [2,154] that increases further with disease severity [154].…”

Section: Ace2 and Potential Cardiovascular Risk Factorsmentioning

confidence: 86%

SARS-CoV-2, ACE2, and Hydroxychloroquine: Cardiovascular Complications, Therapeutics, and Clinical Readouts in the Current Settings

et al. 2020

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The rapidly evolving coronavirus disease 2019 (COVID-19, caused by severe acute respiratory syndrome coronavirus 2- SARS-CoV-2), has greatly burdened the global healthcare system and led it into crisis in several countries. Lack of targeted therapeutics led to the idea of repurposing broad-spectrum drugs for viral intervention. In vitro analyses of hydroxychloroquine (HCQ)’s anecdotal benefits prompted its widespread clinical repurposing globally. Reports of emerging cardiovascular complications due to its clinical prescription are revealing the crucial role of angiotensin-converting enzyme 2 (ACE2), which serves as a target receptor for SARS-CoV-2. In the present settings, a clear understanding of these targets, their functional aspects and physiological impact on cardiovascular function are critical. In an up-to-date format, we shed light on HCQ’s anecdotal function in stalling SARS-CoV-2 replication and immunomodulatory activities. While starting with the crucial role of ACE2, we here discuss the impact of HCQ on systemic cardiovascular function, its associated risks, and the scope of HCQ-based regimes in current clinical settings. Citing the extent of HCQ efficacy, the key considerations and recommendations for the use of HCQ in clinics are further discussed. Taken together, this review provides crucial insights into the role of ACE2 in SARS-CoV-2-led cardiovascular activity, and concurrently assesses the efficacy of HCQ in contemporary clinical settings.

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Rosiglitazone, a Ligand to PPARγ, Improves Blood Pressure and Vascular Function through Renin-Angiotensin System Regulation

Cited by 26 publications

References 44 publications

Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy

Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy

COVID-19, ACE2, and the cardiovascular consequences

SARS-CoV-2, ACE2, and Hydroxychloroquine: Cardiovascular Complications, Therapeutics, and Clinical Readouts in the Current Settings

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