Activation pattern of ACE2/Ang-(1–7) and ACE/Ang II pathway in course of heart failure assessed by multiparametric MRI in vivo in Tgαq*44 mice

Abstract

Here, we analyzed systemic (plasma) and local (heart/aorta) changes in ACE/ACE-2 balance in Tgαq*44 mice in course of heart failure (HF). Tgαq*44 mice with cardiomyocyte-specific Gαq overexpression and late onset of HF were analyzed at different age for angiotensin pattern in plasma, heart, and aorta using liquid chromatography/mass spectrometry, for progression of HF by in vivo magnetic resonance imaging under isoflurane anesthesia, and for physical activity by voluntary wheel running. Six-month-old Tgαq*44 mice displayed decreased ventricle radial strains and impaired left atrial function. At 8-10 mo, Tgαq*44 mice showed impaired systolic performance and reduced voluntary wheel running but exhibited preserved inotropic reserve. At 12 mo, Tgαq*44 mice demonstrated a severe impairment of basal cardiac performance and modestly compromised inotropic reserve with reduced voluntary wheel running. Angiotensin analysis in plasma revealed an increase in concentration of angiotensin-(1-7) in 6- to 10-mo-old Tgαq*44 mice. However, in 12- to 14-mo-old Tgαq*44 mice, increased angiotensin II was noted with a concomitant increase in Ang III, Ang IV, angiotensin A, and angiotensin-(1-10). The pattern of changes in the heart and aorta was also compatible with activation of ACE2, followed by activation of the ACE pathway. In conclusion, mice with cardiomyocyte Gαq protein overexpression develop HF that is associated with activation of the systemic and the local ACE/Ang II pathway. However, it is counterbalanced by a prominent ACE2/Ang-(1-7) activation, possibly allowing to delay decompensation. NEW & NOTEWORTHY Changes in ACE/ACE-2 balance were analyzed based on measurements of a panel of nine angiotensins in plasma, heart, and aorta of Tgαq*44 mice in relation to progression of heart failure (HF) characterized by multiparametric MRI and exercise performance. The early stage of HF was associated with upregulation of the ACE2/angiotensin-(1-7) pathway, whereas the end-stage HF was associated with downregulation of ACE2/angiotensin-(1-7) and upregulation of the ACE/Ang II pathway. ACE/ACE-2 balance seems to determine the decompensation of HF in this model.

Vascular Cognitive Impairment Linked to Brain Endothelium Inflammation in Early Stages of Heart Failure in Mice

“…As early as the fourth month, mRNA for the β‐myosin heavy chain is expressed in cardiomyocytes, indicating activation of fetal genes; cardiac fibrosis is already 4‐fold higher compared to control mice—indicating pathological tissue reorganization and increased compensatory expression of cardiomyocyte desmin, subsequently resulting in extracellular matrix remodeling and sarcomere pathological reorganization as in mechanical stress . Altogether, cardiomyocyte pathology in Tgαq*44 mice, while maintaining normotension, leads to slowly progressing heart deterioration and HF that was previously characterized, but it was not known whether HF in this model results in VCI.…”

“…At the age of 6 months, Tgαq*44 mouse heart function parameters are lower (EF=59%, CO=14.4 mL/min, preserved high‐dose dobutamine response), but global cardiac function is still fully maintained. Yet, at this stage we detect changes characteristic for atrial pathology—lower atrial late flow velocity and subtle diastolic dysfunction of LV—detectable only as decreased myocardial radial strain but not as hemodynamic parameter changes (EF/CO) . At 10 months, global cardiac performance is decreased (ejection rate, fraction area change) .…”

“…Yet, at this stage we detect changes characteristic for atrial pathology—lower atrial late flow velocity and subtle diastolic dysfunction of LV—detectable only as decreased myocardial radial strain but not as hemodynamic parameter changes (EF/CO) . At 10 months, global cardiac performance is decreased (ejection rate, fraction area change) . Therefore, Tgαq*44 mice at the ages of 3, 6, and 10 months represent sequential stages of heart failure development: normal heart, early diastolic, and systolic/diastolic cardiac dysfunction, respectively.…”

“…Therefore, Tgαq*44 mice at the ages of 3, 6, and 10 months represent relatively early stages of HF development. At the age of 4 months, Tgαq*44 mice have preserved global cardiac function (EF=63%, cardiac output [CO]=15 mL/min, preserved high‐dose dobutamine response) and show no functional difference from age‐matched control FVB mice; hence, younger‐than‐3‐month Tgαq*44 mice represent a functionally normal heart . At the age of 6 months, Tgαq*44 mouse heart function parameters are lower (EF=59%, CO=14.4 mL/min, preserved high‐dose dobutamine response), but global cardiac function is still fully maintained.…”

“…In this study we assessed (1) whether slowly progressing heart pathology—before the development of LV systolic dysfunction and end‐stage HF—leads to VCI, and (2) what roles the 2 previously proposed major cardiac pathomechanisms—global cerebral hypoperfusion and prothrombotic condition—play in VCI development. We employed Tgαq*44 mice in which HF develops due to slowly progressing cardiomyopathy, which mimics human HF on a molecular, morphological, phenotypic, and functional level . Their pathology is triggered by postnatal activation of a cardiomyocyte‐specific transgene, causing agonist‐independent, constitutive activation of the Gαq pathway, present only in cardiomyocytes .…”