Abstract 394: Angiotensin II Mediated Increase in Hypertension and Cardiac Hypertrophy in MyD88 Knockout Mice

Toll-like receptors (TLR) are a class of pattern-recognizing receptors (PRR) that play a central role in the innate immune response during infection and sterile injury. MyD88 is an adapter protein that mediates the majority of TLR responses. Since inflammation is a coexisting condition in several cardiovascular diseases, TLRs are thought to play a major role in these conditions. We have previously shown that indeed post-MI survival was significantly improved and cardiac fibrosis and hypertrophy were reduced in MyD88-/- mice (Singh et al. 2012. JMCC). In this study we tested whether angiotensin II (AngII) hypertension and cardiac hypertrophy depended on TLR signaling pathways mediated by MyD88. Male MyD88-/- mice and C57BL/6 mice of 10 to 12 weeks of age were subcutaneously implanted with osmotic minipumps (Alzet) eluting saline or AngII (Sigma, 733 ng/kg/min). Tailcuff pressures were measured with BP2000 (Visitech Systems). Mice were sacrificed after 3 weeks of AngII infusion and hearts were collected for weighing and gene expression analyses. In control WT mice, mean arterial pressure (MAP) remained near baseline levels during the first week of infusion averaging 71± 2 mm Hg and then increased to an average of 100 ± 3 mm Hg and 102 ± 2 mm Hg during the 2nd and 3rd weeks of infusions, respectively. In MyD88-/- mice, MAP increased from a baseline of 84 ± 3 to a high of 120 ± 7 mm Hg during the first week and then declined to 109 ± 6 and 91 ± 9 mm Hg during the 2nd and 3rd weeks. The heart weight to body weight ratios (HW/BW x 1000) after 3 weeks of AngII infusion were not significantly different between WT (5.23 ± 0.15) and MyD88-/- (4.76 ± 0.16). Increases in cardiac hypertrophic marker gene Acta1 were up 4-fold in both WT and MyD88-/- mice, and increases in proinflammatory TNF-alpha, IL-1β, and Nox4 were seen in both genotypes, but the increase in TNF-alpha was significantly greater in MyD88-/- mice. We conclude that unlike post- MI cardiac hypertrophy, the AngII cardiac hypertrophy is not MyD88 -dependent, yet the delayed Ang II pressor response is abrogated in the absence of MyD88. The delayed pressor response to AngII infusion is likely dependent on the immune system.

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Abstract 162: Cardiac Overexpression of Senescence Marker Protein 30 Inhibits Angiotensin II-Induced Cardiac Hypertrophy and Remodeling

Circulation Research ◽

10.1161/res.111.suppl_1.a162 ◽

2012 ◽

Vol 111 (suppl_1) ◽

Author(s):

Tomofumi Misaka ◽

Satoshi Suzuki ◽

Makiko Miyata ◽

Atsushi Kobayashi ◽

Shu-ichi Saitoh ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Fibrosis ◽

Mrna Level ◽

Protective Role ◽

Left Ventricular ◽

Heart Weight ◽

Ang Ii ◽

Marker Protein ◽

Aging Effects

Backgrounds: Senescence marker protein 30 (SMP30) was originally identified as an important aging marker protein, and assumed to behave as an anti-aging factor. Previously, we demonstrated that deficiency of SMP30 exacerbates angiotensin II (Ang II)-induced reactive oxygen species (ROS) and cardiac adverse remodeling, suggesting that SMP30 may have a protective role in the heart. Thus, this study aimed to test the hypothesis that up-regulation of SMP30 inhibits cardiac hypertrophy and remodeling in response to Ang II. Methods: We generated transgenic (SMP30-TG) mice with cardiac-specific overexpression of SMP30 gene using α-myosin heavy chain promoter. SMP30-TG mice and wild type littermate (WT) were subjected to continuous Ang II infusion (800 ng/kg/min). Results: After 2 weeks, heart weight was significantly lower in SMP30-TG mice than in WT mice (P<0.01). Echocardiography revealed that calculated left ventricular mass and E/e’ were lower in SMP30-TG mice than in WT mice (P<0.01 and P<0.05, respectively), suggesting that diastolic function was preserved in SMP30-TG mice. Histological analysis showed that the degree of cardiac fibrosis was significantly decreased in SMP30-TG mice than in WT mice (P<0.05). Dihydroethidium staining demonstrated that generation of ROS was reduced in SMP30-TG mice compared with WT mice (P<0.05). Furthermore, the numbers of senescence-associated β-galactosidase-positive cardiomyocytes were decreased in SMP30-TG mice compared to WT mice (P<0.05). In addition, p21 mRNA level was significantly suppressed in SMP30-TG mice compared to WT mice (P<0.01). Conclusions: This study demonstrated cardiac-specific overexpression of SMP30 inhibits Ang II-induced cardiac hypertrophy and remodeling. These findings suggested that SMP30 has a cardio-protective role with anti-oxidative and anti-aging effects. Up-regulation of SMP30 might be a new strategy to approach senescent cardiac diseases and attenuate the development of heart failure particularly with hypertension.

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Abstract 1221: Targeted Deletion of ROCK2 in Cardiomyocytes Prevents Angiotensin II-Induced Cardiac Hypertrophy

Circulation ◽

10.1161/circ.116.suppl_16.ii_248-a ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Ryuji Okamoto ◽

Kensuke Noma ◽

Naoki Sawada ◽

Yukio Hiroi ◽

Ping-Yen Liu ◽

...

Keyword(s):

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cardiac Fibrosis ◽

Systolic Function ◽

Left Ventricular ◽

Mitogen Activated Protein Kinase ◽

Heart Weight ◽

Ang Ii ◽

Targeted Deletion

Background - Previous studies have shown that Rho kinase (ROCK) inhibitors prevent the development of cardiac hypertrophy. Because ROCK inhibitors inhibit both ROCK isoforms, ROCK1 and ROCK2, the isoform-specific role of ROCK cannot be elucidated from these studies. Hence, a genetic approach with targeted deletion of ROCK in cardiomyocytes provides the best opportunity towards understanding the role of ROCK isoforms in the development of cardiac hypertrophy. Previous studies showed that ROCK1 KO mice develop cardiac hypertrophy to angiotensin II infusion similar to WT mice, but do not develop cardiac fibrosis. However, the role of ROCK2 in the development of cardiac hypertrophy remains to be determined. Methods and Results - Mice deficient in cardiomyocyte-specific ROCK2 (c-ROCK2 −/− ) were generated by crossing mice with loxP-flanked ROCK2 allele with transgenic mice expressing a Cre protein under the control of the cardiomyocyte-specific alpha-myosin heavy chain promoter. The ROCK2 expression levels in the c-ROCK2 −/− mice heart was decreased to less than 30% compared with wild-type mice (ROCK2 +/+ mice) in the whole heart. Heart rate, blood pressures and cardiac systolic function were normal in c-ROCK2 −/− mice. Ang II (400ng/kg/min) or vehicle was subcutaneously infused into c-ROCK2 −/− and ROCK2 +/+ male mice (each group; n=10) for 28 days. Ang II-induced cardiac hypertrophy assessed by an increase in heart weight, left ventricular mass, myocyte cross-sectional area and cardiac hypertrophy-related genes expressions were attenuated in c-ROCK2 −/− mice compared with ROCK2 +/+ mice. The basal activity of extracellular signal-regulated kinase (ERK) were similar in hearts between two groups but the activation of ERK was attenuated and the activity was downregulated earlier in c-ROCK2 −/− than in ROCK2 +/+ mice. The activity of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (p38 MAPK) and Akt activity were similar between two groups. Conclusions - These results indicate that ROCK2 is necessary for Ang II-induced cardiac hypertrophy. The mechanism, in part, involves the activation of ERK by ROCK2. Thus, selective ROCK2 inhibitors may be beneficial for preventing cardiac hypertrophy.

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Abstract 19953: Interactions of MyD88 and TRIF-Pathways of Innate Immune Responses Regulate Angiotensin II Hypertension

Circulation ◽

10.1161/circ.132.suppl_3.19953 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Madhu V Singh ◽

Michael Z Cicha ◽

Mark W Chapleau ◽

François M Abboud

Keyword(s):

Angiotensin Ii ◽

Inflammatory Responses ◽

Pressor Response ◽

Alternative Pathway ◽

Weight Ratio ◽

Adaptor Protein ◽

Adaptor Proteins ◽

Innate Immune ◽

Heart Weight ◽

Ang Ii

We have reported that angiotensin II (Ang II) induces toll-like receptors (TLRs) in the innate immune system. Here we tested which of the two major adaptor proteins of TLRs, the myeloid differentiation protein 88 (MyD88) or the TIR-domain containing adaptor inducing interferon β (TRIF) mediates the Ang II-induced responses. Infusion of Ang II (3000 ng/kg/min) subcutaneously for 3 weeks in WT mice (C57BL/6J) increased systolic blood pressure to a peak value of 147 ± 4 mm Hg and resulted in a 40% increase in heart weight to body weight ratio (HW/BW). Surprisingly, in MyD88-/- mice the pressor response was enhanced significantly to 163 ± 6 mm Hg (P<0.05) and the HW/BW was increased by 60%. Cardiac and renal RNA expression of TNF-α, NOX4 and Type IA -Ang II receptor were also significantly more elevated in MyD88-/- than in WT. In contrast, in a mouse strain with nonfunctional TRIF gene, Trifmut (C57BL/6J-Ticam1Lps2/J), all the Ang II responses were either uniformly decreased or abrogated. We tested whether the enhanced response in MyD88-/- mice represented a phenomenon of ‘Signaling Flux Redistribution” whereby blockade of one signaling pathway (i.e., MyD88) results in a flux of signaling substrates through the alternative pathway (TRIF). We found that expression of the RNA for chemokine CXCL10 which is dependent on TRIF pathway, was significantly enhanced in MyD88-/- hearts. We also found that expression of transcripts for TLR3, TLR4 and the TRIF adaptor protein were all enhanced in MyD88-/- and must have contributed to the exaggerated Ang II response. Conversely, Trifmut had enhanced MyD88 expression. These results suggest that: (1) Ang II induced hypertension, hypertrophy and inflammatory gene expression are primarily mediated by the TRIF pathway and (2) the MyD88 pathway is simultaneously activated by Ang II and exerts a negative regulatory influence on the pressor and inflammatory responses. We conclude that dual activation of two innate immune pathways defines the net response in WT mice with a significant translational potential. Accordingly, impairment of MyD88 may contribute to pathogenesis of hypertension. Conversely, targeting the TRIF pathway may be therapeutic by blocking the inflammatory response and enhancing the negative regulatory effects of MyD88.

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KLK11 promotes the activation of mTOR and protein synthesis to facilitate cardiac hypertrophy

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-02053-y ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yi Wang ◽

Hongjuan Liao ◽

Yueheng Wang ◽

Jinlin Zhou ◽

Feng Wang ◽

...

Keyword(s):

Protein Synthesis ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Western Blot ◽

Real Time ◽

Real Time Pcr ◽

Mtor Signaling ◽

Heart Weight ◽

Cardiomyocyte Hypertrophy ◽

Quantitative Real Time Pcr

Abstract Background Cardiovascular diseases have become the leading cause of death worldwide, and cardiac hypertrophy is the core mechanism underlying cardiac defect and heart failure. However, the underlying mechanisms of cardiac hypertrophy are not fully understood. Here we investigated the roles of Kallikrein 11 (KLK11) in cardiac hypertrophy. Methods Human and mouse hypertrophic heart tissues were used to determine the expression of KLK11 with quantitative real-time PCR and western blot. Mouse cardiac hypertrophy was induced by transverse aortic constriction (TAC), and cardiomyocyte hypertrophy was induced by angiotensin II. Cardiac function was analyzed by echocardiography. The signaling pathway was analyzed by western blot. Protein synthesis was monitored by the incorporation of [3H]-leucine. Gene expression was analyzed by quantitative real-time PCR. Results The mRNA and protein levels of KLK11 were upregulated in human hypertrophic hearts. We also induced cardiac hypertrophy in mice and observed the upregulation of KLK11 in hypertrophic hearts. Our in vitro experiments demonstrated that KLK11 overexpression promoted whereas KLK11 knockdown repressed cardiomyocytes hypertrophy induced by angiotensin II, as evidenced by cardiomyocyte size and the expression of hypertrophy-related fetal genes. Besides, we knocked down KLK11 expression in mouse hearts with adeno-associated virus 9. Knockdown of KLK11 in mouse hearts inhibited TAC-induced decline in fraction shortening and ejection fraction, reduced the increase in heart weight, cardiomyocyte size, and expression of hypertrophic fetal genes. We also observed that KLK11 promoted protein synthesis, the key feature of cardiomyocyte hypertrophy, by regulating the pivotal machines S6K1 and 4EBP1. Mechanism study demonstrated that KLK11 promoted the activation of AKT-mTOR signaling to promote S6K1 and 4EBP1 pathway and protein synthesis. Repression of mTOR with rapamycin blocked the effects of KLK11 on S6K1 and 4EBP1 as well as protein synthesis. Besides, rapamycin treatment blocked the roles of KLK11 in the regulation of cardiomyocyte hypertrophy. Conclusions Our findings demonstrated that KLK11 promoted cardiomyocyte hypertrophy by activating AKT-mTOR signaling to promote protein synthesis.

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Activated myofibroblasts promote cardiac hypertrophy and systolic dysfunction independently of cardiac fibrosis in experimental autoimmune myocarditis

European Heart Journal ◽

10.1093/eurheartj/ehab724.3328 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

Author(s):

K Tkacz ◽

A Jazwa-Kusior ◽

F Rolski ◽

E Dzialo ◽

K Weglarczyk ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Dilated Cardiomyopathy ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Systolic Dysfunction ◽

Heart Weight ◽

Type I ◽

Autoimmune Myocarditis ◽

Experimental Autoimmune Myocarditis ◽

Experimental Autoimmune

Abstract Background/Introduction Heart-specific inflammation – myocarditis is a common cause dilated cardiomyopathy which is characterized by pathological tissue remodeling, ventricular stiffening, cardiomyopathy and heart failure. In experimental autoimmune myocarditis (EAM) susceptible mice immunized with alpha myosin heavy chain (αMyHC) and complete Freund's adjuvant (CFA) develop acute myocarditis driven by autoreactive CD4+ T cells that is followed by progressive fibrosis, cardiomyopathy and systolic dysfunction. Purpose The aim of the study was to investigate the role of cardiac fibroblasts and myofibroblasts in myocarditis and post-inflammatory dilated cardiomyopathy in mouse model of EAM. Methods EAM was induced in BALB/c mice by immunization with αMyHC/CFA. We used reporter mice expressing EGFP under collagen type I promoter (Coll-EGFP) and RFP under a control of α-smooth muscle actin (αSMA) promoter (αSMA-RFP) and transgenic αSMA-TK mice with ganciclovir-inducible ablation of proliferating myofibroblasts. Cardiac cells were quantified using flow cytometry. Cardiac fibroblasts (CD45-CD31-EGFP+) were sorted from healthy and myocarditis-positive (day 21) mice using BD FACSAria™ II Cell Sorter and analyzed for the whole genome transcriptomics by RNA sequencing. Echocardiography was performed on Vevo 2100 Imaging System. Cardiac fibrosis was assessed by Trichrome Massons's staining and hydroxyproline assay, whereas cardiac hypertrophy by analysing cross-sectional cardiomyocyte area. Profibrotic gene expression was assessed by qRT-PCR. Results The total number of cardiac fibroblasts (CD45-CD31-EGFP+) and the subset of myofibroblasts (CD45-CD31-EGFP+RFP+) remained unchanged at inflammatory (d21) and fibrotic stages (d40). Analysis of differentially expressed genes (min. 2x fold change, p value <0.05) pointed out activation of immune processes (mainly chemokine production), response to stress, cytoskeletal and extracellular matrix re-organization in cardiac fibroblasts in response to myocarditis. αSMA-TK mice treated with ganciclovir (from day 21) showed comparable percent of fibrotic area, but significantly reduced heart weight, decreased cardiomyocyte hypertrophy and improved ejection fraction and cardiac output at day 40 comparing to PBS-treated mice. Ganciclovir-treated mice showed also attenuated cardiac Acta2 and Srf but markedly enhanced Mmp2 expression. Conclusions In EAM model cardiac fibroblasts actively participate in proinflammatory and profibrotic responses, while activated myofibroblasts contribute to dilated cardiomyopathy development independently of cardiac fibrosis. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Science Centre (Poland)

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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.

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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.

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Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01124.2005 ◽

2006 ◽

Vol 291 (4) ◽

pp. H1545-H1553 ◽

Cited By ~ 73

Author(s):

Jyothish B. Pillai ◽

Madhu Gupta ◽

Senthilkumar B. Rajamohan ◽

Roberto Lang ◽

Jai Raman ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Angiotensin Ii ◽

Cardiac Hypertrophy ◽

Cell Signaling ◽

Primary Cultures ◽

Heart Weight ◽

Cell Protein ◽

Sequence Of Events ◽

Deficient Mice

Poly(ADP-ribose) polymerase-1 (PARP), a chromatin-bound enzyme, is activated by cell oxidative stress. Because oxidative stress is also considered a main component of angiotensin II-mediated cell signaling, it was postulated that PARP could be a downstream target of angiotensin II-induced signaling leading to cardiac hypertrophy. To determine a role of PARP in angiotensin II-induced hypertrophy, we infused angiotensin II into wild-type (PARP+/+) and PARP-deficient mice. Angiotensin II infusion significantly increased heart weight-to-tibia length ratio, myocyte cross-sectional area, and interstitial fibrosis in PARP+/+ but not in PARP−/− mice. To confirm these results, we analyzed the effect of angiotensin II in primary cultures of cardiomyocytes. When compared with PARP−/− cardiomyocytes, angiotensin II (1 μM) treatment significantly increased protein synthesis in PARP+/+ myocytes, as measured by 3H-leucine incorporation into total cell protein. Angiotensin II-mediated hypertrophy of myocytes was accompanied with increased poly-ADP-ribosylation of nuclear proteins and depletion of cellular NAD content. When cells were treated with cell death-inducing doses of angiotensin II (10–20 μM), robust myocyte cell death was observed in PARP+/+ but not in PARP−/− myocytes. This type of cell death was blocked by repletion of cellular NAD levels as well as by activation of the longevity factor Sir2α deacetylase, indicating that PARP induction and subsequent depletion of NAD levels are the sequence of events causing angiotensin II-mediated cardiomyocyte cell death. In conclusion, these results demonstrate that PARP is a nuclear integrator of angiotensin II-mediated cell signaling contributing to cardiac hypertrophy and suggest that this could be a novel therapeutic target for the management of heart failure.

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

Physiological Genomics ◽

10.1152/physiolgenomics.00170.2004 ◽

2004 ◽

Vol 19 (3) ◽

pp. 255-261 ◽

Cited By ~ 41

Author(s):

Beverly L. Falcón ◽

Jillian M. Stewart ◽

Erick Bourassa ◽

Michael J. Katovich ◽

Glenn Walter ◽

...

Keyword(s):

Angiotensin Ii ◽

Gene Transfer ◽

Cardiac Hypertrophy ◽

Rat Model ◽

Lentiviral Vector ◽

Receptor Gene ◽

Left Ventricular ◽

Heart Weight ◽

Sprague Dawley

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.

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