Angiotensin II type 2 receptor gene transfer elicits cardioprotective effects in an angiotensin II infusion rat model of hypertension

The role of the angiotensin II type 2 receptor (AT2R) in cardiovascular physiology remains elusive. We have developed an in vivo lentiviral vector-mediated gene transfer system to study the physiological functions of the AT2R. Our objectives in this study were to determine whether the AT2R influences cardiac hypertrophy and myocardial and perivascular fibrosis in a nongenetic rat model of hypertension. Lentiviral vector containing the AT2R or saline was injected intracardially in 5-day-old Sprague-Dawley rats. This resulted in a persistent overexpression of the AT2R in cardiac tissues. At 15 wk of age, animals were infused with either 200 ng·kg−1·min−1 of angiotensin II or saline by implantation of a 4-wk osmotic minipump. This resulted in an increase in blood pressure (BP) that reached maximal by 2 wk of treatment and was associated with a 123% increase in left ventricular wall thickness (LVWT) and a 129% increase in heart weight to body weight ratios (HW/BW). In addition, the increase in cardiac hypertrophy was associated with a 300% and 158% increase in myocardial and perivascular fibrosis, respectively. Cardiac transduction of the AT2R resulted in an 85% attenuation of LVWT, 91% attenuation of HW/BW, and a 43% decrease in myocardial fibrosis induced by angiotensin infusion. These improvements in cardiac pathology were observed in the absence of attenuation of high BP. Thus our observations indicate that long-term expression of the AT2R in the heart attenuates cardiac hypertrophy and fibrosis in a nongenetic rat model of hypertension.

Download Full-text

Prevention of Cardiac Hypertrophy by Angiotensin II Type-2 Receptor Gene Transfer

Hypertension ◽

10.1161/01.hyp.0000127563.14064.fd ◽

2004 ◽

Vol 43 (6) ◽

pp. 1233-1238 ◽

Cited By ~ 45

Author(s):

Beverly L. Metcalfe ◽

Matthew J. Huentelman ◽

Leonard D. Parilak ◽

David G. Taylor ◽

Michael J. Katovich ◽

...

Keyword(s):

Angiotensin Ii ◽

Gene Transfer ◽

Cardiac Hypertrophy ◽

Receptor Gene

Download Full-text

Abstract 478: FGF23 Expression in Cardiac Fibroblasts Is Augmented by S100/Calgranulins-Mediated Inflammation and Associated With Cardiac Hypertrophy, but Not in Angiotensin II-Induced Cardiac Hypertrophy

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.478 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Marion Hofmann Bowman ◽

Brandon Gardner ◽

Judy Earley ◽

Debra L Rateri ◽

Alan Daugherty ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Fibroblasts ◽

Left Ventricular ◽

Heart Weight ◽

Ang Ii ◽

Wild Type ◽

Wild Type Littermate ◽

Transgenic Expression ◽

Significant Difference

Background: Serum S100A12 and fibroblast growth factor (FGF) 23 are biomarkers for cardiovascular mortality in patients with chronic kidney disease (CKD) and are associated with left ventricular hypertrophy (LVH). FGF23 is induced in cultured cardiac fibroblasts in response to cytokines including IL-6, TNF-a, LPS and S100/calgranulins. Moreover, hBAC-S100 transgenic mice with CKD had increased FGF23 in valvular interstitial cells and exhibited LVH. The present study was designed to examine cardiac FGF23 expression in other murine models of LVH in the absence of CKD. Methods: Hearts from five groups of male mice were studied: (i) C57BL6/J with transgenic expression a bacterial artificial chromosome of the human S100/calgranulins (S1008/9 and S100A12, hBAC-S100), (ii) wild type littermates, (iii) LDLR-/- infused with saline (29 days, 0.9%), (iv) LDLR-/- infused with angiotensin (Ang) II (29 days, 1000 ng/kg/min), and (v) fibroblast specific depletion of angiotensin II type 1a receptor (AT1aR) (S100A4-Cre x AT1aR-/- x LDLR-/-) infused with AngII. Results: hBAC-S100, but not wild type littermate mice, developed significant LVH at 10 months by heart weight/body weight (5.9 ±1.1 mg/g vs. 4.2 ±0.8, p<0.04), decreased E/A ratio, and increased LVPW thickness, and associated with increased expression of FGF23 mRNA and protein in cardiac tissue lysates (2-4 fold increase). Similarly, Ang II induced significant LVH compared to saline infused LDLR-/- mice (6.1±1.3 vs. 3.6 ±0.9 mg/g, p<0.01), and associated with increased mRNA for hypertrophic genes (ANP, BNP, b-MHC, CTGF and Col1a1). However, there was no significant difference in FGF23 mRNA and protein between Ang II and saline infused mice. Cardiac hypertrophy was attenuated in AngII-infused mice with deficiency of AT1aR (S100A4-Cre+/-xAT1aRxLDLR-/-). In vitro, Ang II (100nM) did not induce FGF23 in valvular interstitial fibroblasts or myocytes. Summary: Transgenic expression of S100/calgranulins is sufficient to induce LVH in aged mice with normal renal function, and this is associated with FGF23 expression in cardiac interstitial fibroblasts. Future studies are needed to determine whether cardiac FGF23 promotes LVH in a paracrine manner. However, FGF23 does not play a role in Ang II-induced LVH.

Download Full-text

Rat model of exercise-induced cardiac hypertrophy: hemodynamic characterization using left ventricular pressure-volume analysis

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00108.2013 ◽

2013 ◽

Vol 305 (1) ◽

pp. H124-H134 ◽

Cited By ~ 31

Author(s):

Tamás Radovits ◽

Attila Oláh ◽

Árpád Lux ◽

Balázs Tamás Németh ◽

László Hidi ◽

...

Keyword(s):

Exercise Training ◽

Cardiac Hypertrophy ◽

Rat Model ◽

Left Ventricular ◽

Heart Weight ◽

Stroke Work ◽

Functional Changes ◽

Exercise Induced

Long-term exercise training is associated with characteristic structural and functional changes of the myocardium, termed athlete's heart. Several research groups investigated exercise training-induced left ventricular (LV) hypertrophy in animal models; however, only sporadic data exist about detailed hemodynamics. We aimed to provide functional characterization of exercise-induced cardiac hypertrophy in a rat model using the in vivo method of LV pressure-volume (P-V) analysis. After inducing LV hypertrophy by swim training, we assessed LV morphometry by echocardiography and performed LV P-V analysis using a pressure-conductance microcatheter to investigate in vivo cardiac function. Echocardiography showed LV hypertrophy (LV mass index: 2.41 ± 0.09 vs. 2.03 ± 0.08 g/kg, P < 0.01), which was confirmed by heart weight data and histomorphometry. Invasive hemodynamic measurements showed unaltered heart rate, arterial pressure, and LV end-diastolic volume along with decreased LV end-systolic volume, thus increased stroke volume and ejection fraction (73.7 ± 0.8 vs. 64.1 ± 1.5%, P < 0.01) in trained versus untrained control rats. The P-V loop-derived sensitive, load-independent contractility indexes, such as slope of end-systolic P-V relationship or preload recruitable stroke work (77.0 ± 6.8 vs. 54.3 ± 4.8 mmHg, P = 0.01) were found to be significantly increased. The observed improvement of ventriculoarterial coupling (0.37 ± 0.02 vs. 0.65 ± 0.08, P < 0.01), along with increased LV stroke work and mechanical efficiency, reflects improved mechanoenergetics of exercise-induced cardiac hypertrophy. Despite the significant hypertrophy, we observed unaltered LV stiffness (slope of end-diastolic P-V relationship: 0.043 ± 0.007 vs. 0.040 ± 0.006 mmHg/μl) and improved LV active relaxation (τ: 10.1 ± 0.6 vs. 11.9 ± 0.2 ms, P < 0.01). According to our knowledge, this is the first study that provides characterization of functional changes and hemodynamic relations in exercise-induced cardiac hypertrophy.

Download Full-text

A Reduction in ADAM17 Expression Is Involved in the Protective Effect of the PPAR-α Activator Fenofibrate on Pressure Overload-Induced Cardiac Hypertrophy

PPAR Research ◽

10.1155/2018/7916953 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 2

Author(s):

Si-Yu Zeng ◽

Hui-Qin Lu ◽

Qiu-Jiang Yan ◽

Jian Zou

Keyword(s):

Body Weight ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Wall Thickness ◽

Protective Action ◽

Pressure Overload ◽

Left Ventricular ◽

Heart Weight ◽

Hypertensive Rats ◽

Protein Levels

The peroxisome proliferator-activated receptor-α (PPAR-α) agonist fenofibrate ameliorates cardiac hypertrophy; however, its mechanism of action has not been completely determined. Our previous study indicated that a disintegrin and metalloproteinase-17 (ADAM17) is required for angiotensin II-induced cardiac hypertrophy. This study aimed to determine whether ADAM17 is involved in the protective action of fenofibrate against cardiac hypertrophy. Abdominal artery constriction- (AAC-) induced hypertensive rats were used to observe the effects of fenofibrate on cardiac hypertrophy and ADAM17 expression. Primary cardiomyocytes were pretreated with fenofibrate (10 μM) for 1 hour before being stimulated with angiotensin II (100 nM) for another 24 hours. Fenofibrate reduced the ratios of left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW), left ventricular anterior wall thickness (LVAW), left ventricular posterior wall thickness (LVPW), and ADAM17 mRNA and protein levels in left ventricle in AAC-induced hypertensive rats. Similarly, in vitro experiments showed that fenofibrate significantly attenuated angiotensin II-induced cardiac hypertrophy and diminished ADAM17 mRNA and protein levels in primary cardiomyocytes stimulated with angiotensin II. In summary, a reduction in ADAM17 expression is associated with the protective action of PPAR-α agonists against pressure overload-induced cardiac hypertrophy.

Download Full-text

Context-dependent effects of the angiotensin II type 2 receptor gene on left ventricular remodelling: the story continues

Journal of Hypertension ◽

10.1097/hjh.0b013e32833ae553 ◽

2010 ◽

Vol 28 (6) ◽

pp. 1124-1126

Author(s):

Tatiana Kuznetsova

Keyword(s):

Angiotensin Ii ◽

Receptor Gene ◽

Left Ventricular ◽

Ventricular Remodelling ◽

Left Ventricular Remodelling ◽

Context Dependent

Download Full-text

Captopril prevents vascular and fibrotic changes but not cardiac hypertrophy in aortic-banded rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.3.h906 ◽

1996 ◽

Vol 271 (3) ◽

pp. H906-H913 ◽

Cited By ~ 4

Author(s):

C. P. Regan ◽

P. G. Anderson ◽

S. P. Bishop ◽

K. H. Berecek

Keyword(s):

Cardiac Hypertrophy ◽

Coronary Vessels ◽

Pressure Overload ◽

Renin Angiotensin System ◽

Left Ventricular ◽

Heart Weight ◽

Sprague Dawley ◽

Vessel Morphology ◽

Sprague Dawley Rats ◽

Quantitative Image

To determine the role of the renin-angiotensin system (RAS) on cardiovascular remodeling in a pressure overload model of cardiac hypertrophy, a subdiaphragmatic aortic band was placed in adult male, Sprague-Dawley rats. Rats were left untreated (AB) or given captopril (Cap, 400 mg/l) (AB-Cap). Sham-operated controls were either left untreated (S) or given Cap (S-Cap). After 4 wk, rats were catheterized, and carotid and femoral mean arterial pressures (CMAP and FMAP in mmHg, respectively) were recorded. Hearts were isolated, and minimal coronary resistance (MCR) was determined. Hearts were then perfusion fixed, total and regional heart weights were recorded, and sections were processed for vessel morphology. Changes in coronary artery medical thickness and perivascular fibrosis were assessed by quantitative image analysis. CMAP was significantly higher in AB and AB-Cap than S or S-Cap rats (P < 0.05). There was no difference in FMAP in AB vs. S rats, but AB-Cap and S-Cap had lower FMAP values than S rats. Total heart weight and left ventricular weight-to-body weight ratios were increased in AB and AB-Cap rats compared with S and S-Cap rats (P < 0.05). MCR of AB was greater than S and S-Cap rats. MCR of AB-Cap rats was significantly greater than S and S-Cap rats but was significantly less than AB rats. In coronary vessels, medial thickness was greatest in AB, whereas there was no difference among AB-Cap, S, and S-Cap rats. Similarly, the increase in perivascular fibrosis was greatest in AB rats, and there was no difference among AB-Cap, S, and S-Cap rats. These data suggest that the RAS, independent of increased arterial pressure, is critical for the development of the vascular and fibrotic changes that occur in this model of pressure overload hypertrophy.

Download Full-text

ANGIOTENSIN II TYPE 2 RECEPTOR GENE TRANSFER ELICITS CARDIOPROTECTIVE EFFECTS

Journal of Hypertension ◽

10.1097/00004872-200406002-00594 ◽

2004 ◽

Vol 22 (Suppl. 2) ◽

pp. S173

Author(s):

B. L. Metcalfe ◽

M. J. Huentelman ◽

M. J. Katovich ◽

H. J. Knot ◽

C. Sumners ◽

...

Keyword(s):

Angiotensin Ii ◽

Gene Transfer ◽

Receptor Gene ◽

Cardioprotective Effects

Download Full-text

Inhibition of Cardiac Hypertrophy Effects in D-Galactose-Induced Senescent Hearts byAlpinate Oxyphyllae FructusTreatment

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/2624384 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 8

Author(s):

Yung-Ming Chang ◽

Hen-Hong Chang ◽

Hung-Jen Lin ◽

Chin-Chuan Tsai ◽

Chuan-Te Tsai ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Rat Model ◽

Cerebrovascular Disorders ◽

Treated Group ◽

Left Ventricular ◽

Heart Weight ◽

Dependent Manner ◽

Signaling Mechanism ◽

Aging Rat ◽

Whole Heart

Aging is a complex physiological phenomenon accelerated by ROS accumulation, with multisystem decline and increasing vulnerability to degenerative diseases and death. Cardiac hypertrophy is a key pathophysiological component that accompanies the aging process. Alpinate Oxyphyllae Fructus (Alpinia oxyphyllaMIQ, AOF) is a traditional Chinese medicine, which provides cardioprotective activity against aging, hypertension, and cerebrovascular disorders. In this study, we found the protective effect of AOF against cardiac hypertrophy in D-galactose-induced aging rat model. The results showed that treating rats with D-galactose resulted in pathological hypertrophy as evident from the morphology change, increased left ventricular weight/whole heart weight, and expression of hypertrophy-related markers (MYH7 and BNP). Both concentric and eccentric cardiac hypertrophy signaling proteins were upregulated in aging rat model. However, these pathological changes were significantly improved in AOF treated group (AM and AH) in a dose-dependent manner. AOF negatively modulated D-galactose-induced cardiac hypertrophy signaling mechanism to attenuate ventricular hypertrophy. These enhanced cardioprotective activities following oral administration of AOF reflect the potential use of AOF for antiaging treatments.

Download Full-text