Rationale: Excess signaling through cardiac G␥ subunits is an important component of heart failure (HF) pathophysiology. They recruit elevated levels of cytosolic G protein-coupled receptor kinase (GRK)2 to agonist-stimulated -adrenergic receptors (-ARs) in HF, leading to chronic -AR desensitization and downregulation; these events are all hallmarks of HF. Previous data suggested that inhibiting G␥ signaling and its interaction with GRK2 could be of therapeutic value in HF. Objective: We sought to investigate small molecule G␥ inhibition in HF. Methods and Results: We recently described novel small molecule G␥ inhibitors that selectively block G␥-binding interactions, including M119 and its highly related analog, gallein. These compounds blocked interaction of G␥ and GRK2 in vitro and in HL60 cells. Here, we show they reduced -AR-mediated membrane recruitment of GRK2 in isolated adult mouse cardiomyocytes. Furthermore, M119 enhanced both adenylyl cyclase activity and cardiomyocyte contractility in response to -AR agonist. To evaluate their cardiac-specific effects in vivo, we initially used an acute pharmacological HF model (30 mg/kg per day isoproterenol, 7 days). Concurrent daily injections prevented HF and partially normalized cardiac morphology and GRK2 expression in this acute HF model. To investigate possible efficacy in halting progression of preexisting HF, calsequestrin cardiac transgenic mice (CSQ) with extant HF received daily injections for 28 days. The compound alone halted HF progression and partially normalized heart size, morphology, and cardiac expression of HF marker genes (GRK2, atrial natriuretic factor, and -myosin heavy chain). Conclusions: These data suggest a promising therapeutic role for small molecule inhibition of pathological G␥ signaling in the treatment of HF. (Circ Res. 2010;107:532-539.)Key Words: G proteins Ⅲ adrenergic receptor Ⅲ G protein-coupled receptor kinases Ⅲ cardiomyopathy Ⅲ heart failure Ⅲ cardiomyocyte H eart failure (HF) is a devastating disease with poor prognosis, and remains a leading cause of death worldwide. 1,2 Excess signaling through cardiac G protein G␥ subunits is an important component of HF pathophysiology. In particular, they recruit elevated levels of cytosolic G protein-coupled receptor kinase 2 (GRK2) (-adrenergic receptor kinase [-ARK]1) to agonist-stimulated -ARs in HF, 3 leading to the chronic -AR desensitization, downregulation and pathological signaling that are hallmarks of HF. 4,5 Increasing evidence suggests a critical role for G␥-mediated signaling in HF. In particular, GRK2 is significantly upregulated in cardiomyocytes of animal models of HF and human HF patients; this elevates G␥-GRK2 interactions and contributes to chronic desensitization of -AR signaling 6,7 ; interestingly, levels of GRK2 appear to correlate with the severity of HF. 6,8 Enhancing G␥-GRK2 interaction by cardiac targeted overexpression of GRK2(s) can directly cause HF in experimental animal models 9 ; its genetic ablation has generally proven to be...
Rodent models of cardiac pathophysiology represent a valuable research tool to investigate mechanism of disease as well as test new therapeutics. 1 Echocardiography provides a powerful, non-invasive tool to serially assess cardiac morphometry and function in a living animal. 2 However, using this technique on mice poses unique challenges owing to the small size and rapid heart rate of these animals. 3 Until recently, few ultrasound systems were capable of performing quality echocardiography on mice, and those generally lacked the image resolution and frame rate necessary to obtain truly quantitative measurements. Newly released systems such as the VisualSonics Vevo2100 provide new tools for researchers to carefully and non-invasively investigate cardiac function in mice. This system generates high resolution images and provides analysis capabilities similar to those used with human patients. Although color Doppler has been available for over 30 years in humans, this valuable technology has only recently been possible in rodent ultrasound. 4,5 Color Doppler has broad applications for echocardiography, including the ability to quickly assess flow directionality in vessels and through valves, and to rapidly identify valve regurgitation. Strain analysis is a critical advance that is utilized to quantitatively measure regional myocardial function. 6 This technique has the potential to detect changes in pathology, or resolution of pathology, earlier than conventional techniques. Coupled with the addition of three-dimensional image reconstruction, volumetric assessment of whole-organs is possible, including visualization and assessment of cardiac and vascular structures. Murine-compatible contrast imaging can also allow for volumetric measurements and tissue perfusion assessment. Begin by securing an isoflurane anesthetized mouse to an animal-handling platform in the supine position. Place a nose cone over the animal's nose and mouth to deliver 0.5-1% isoflurane to maintain the anesthesia. 2. Secure the paws of the mouse to the electrode pads with conducting gel. Ensure appropriate ECG, body temperature at 37°C and check respiratory rate for physiological assessment during imaging. 3. Apply depilatory cream to the chest and upper abdomen of the mouse. 4. After 2 minutes, use wet gauze remove to the cream.1. Once the mouse has been prepared for imaging, tilt the left side of the platform to rotate the animal handling platform 30 degrees about the anterioposterior axis. 2. Orient the transducer in the vertical position and rotate 10 degrees counterclockwise with the notch pointed toward the posterior of the mouse. 3. Next, while in the two-dimensional viewing/video "B-mode", lower the transducer over the left parasternal line until the heart comes into view.Once the pulmonary artery comes into view, collect images and store them. 4. Still in B-mode, move the transducer left or right until the aortic outflow and apex come into view. Some rotation of the probe may be necessary to ensure proper alignment with t...
Background Pregnant patients with Marfan syndrome (MFS) are at an increased risk for adverse aortic outcomes. While beta-blockers are used to slow aortic root dilatation in non-pregnant MFS patients, the benefit of such therapy in pregnant MFS patients remains controversial. The purpose of this study was to investigate the effect of beta-blockers on aortic root dilatation during pregnancy in MFS patients. Methods This was a longitudinal single-center retrospective cohort study of females with MFS who completed a pregnancy between 2004 and 2020. Clinical, fetal, and echocardiographic data were compared in patients on vs off beta-blockers during pregnancy. Results A total of 20 pregnancies completed by 19 patients were evaluated. Beta-blocker therapy was initiated or continued in 13 (65%) of the 20 pregnancies. Pregnancies on beta-blocker therapy experienced less aortic growth compared to those off beta-blockers (0.10cm [IQR: 0.10-0.20cm] vs 0.30cm [IQR: 0.25-0.35cm]; P=0.03). Using univariate linear regression, maximum systolic blood pressures (SBP), increase in SBP, and absence of beta-blocker use in pregnancy were found to be significantly associated with greater increase in aortic diameter during pregnancy. There were no differences in rates of fetal growth restriction between pregnancies on vs off beta-blockers. Conclusions This is the first study to evaluate changes in aortic dimensions in MFS pregnancies stratified by beta-blocker use. Beta-blocker therapy was found to be associated with less aortic root growth during pregnancy in MFS patients.
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