Loss of PI3Kγ Enhances cAMP-Dependent MMP Remodeling of the Myocardial N-Cadherin Adhesion Complexes and Extracellular Matrix in Response to Early Biomechanical Stress

Guo, Danny; Kassiri, Zamaneh; Basu, Ratnadeep; Chow, Fung L.; Kandalam, Vijay; Damilano, Federico; Liang, Wenbin; Izumo, Seigo; Hirsch, Emilio; Penninger, Josef; Backx, Peter H.; Oudit, Gavin Y.

doi:10.1161/circresaha.110.229054

Cited by 53 publications

(49 citation statements)

References 59 publications

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“…6D and G to I), suggesting that the increase in baseline systolic function in vivo and ventricle wall thickness in MHC-ATGL mice develops with progressing age. We utilized young, 8-to 9-week-old mice for TAC to follow a previously established procedure (14,21,36).…”

Section: Resultsmentioning

confidence: 99%

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Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction

Kienesberger

Pulinilkunnil

Sung

et al. 2012

Molecular and Cellular Biology

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100

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Alterations in myocardial triacylglycerol content have been associated with poor left ventricular function, suggesting that enzymes involved in myocardial triacylglycerol metabolism play an important role in regulating contractile function. Myocardial triacylglycerol catabolism is mediated by adipose triglyceride lipase (ATGL), which is rate limiting for triacylglycerol hydrolysis. To address the influence of triacylglycerol hydrolysis on myocardial energy metabolism and function, we utilized mice with cardiomyocyte-specific ATGL overexpression (MHC-ATGL). Biochemical examination of MHC-ATGL hearts revealed chronically reduced myocardial triacylglycerol content but unchanged levels of long-chain acyl coenzyme A esters, ceramides, and diacylglycerols. Surprisingly, fatty acid oxidation rates were decreased in ex vivo perfused working hearts from MHC-ATGL mice, which was compensated by increased rates of glucose oxidation. Interestingly, reduced myocardial triacylglycerol content was associated with moderately enhanced in vivo systolic function in MHC-ATGL mice and increased isoproterenol-induced cell shortening of isolated primary cardiomyocytes. Most importantly, MHC-ATGL mice were protected from pressure overloadinduced systolic dysfunction and detrimental structural remodeling following transverse aortic constriction. Overall, this study shows that ATGL overexpression is sufficient to alter myocardial energy metabolism and improve cardiac function. Myocardial triacylglycerol (TG) is stored in cytosolic lipid droplets within cardiomyocytes and constitutes a critical fatty acid (FA) and energy reserve for the heart. Metabolism of cardiac TG is highly dynamic (2, 29), which likely evolved as a means to ensure continuous FA supply for mitochondrial oxidation independent of short-term fluctuations in plasma FA availability. Previous studies have shown that FAs released by intracellular TG hydrolysis contribute significantly to the generation of ATP necessary for contractile function (2, 34, 39), suggesting that TG hydrolysis plays a critical role in regulating cardiac function. In agreement with this finding, dysregulation of myocardial TG metabolism and either increased or reduced TG content have been associated with cardiac dysfunction and/or heart failure induced by obesity, diabetes, aging, ischemia, and hemodynamic pressure overload (3,5,8,22,26,(31)(32)(33)(34). Moreover, a clear correlation between increased myocardial TG content and decreased cardiac function has been established in rodents and humans (7,12,22,24), supporting the concept that excessive TG accumulation in the heart is detrimental. On the other hand, it has also been postulated that increasing TG content and sequestration of potentially lipotoxic FA metabolites in the myocardial TG pool can be beneficial for heart function (28, 42). As such, the physiological consequences of preventing myocardial TG accumulation with regard to normal physiology and disease remain to be elucidated.As the enzymes that control TG lipolysis may have an as yet und...

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Section: Resultsmentioning

confidence: 99%

“…Transverse aortic constriction (TAC) was performed as described previously (14). Male 8-to 9-week-old mice were anesthetized by an intraperitoneal injection (0.1 ml/10 g of body weight) of ketamine and xylazine (80 and 12 mg/ml, respectively), intubated, and connected to a mouse ventilator (MiniVent; Harvard Apparatus, Holliston, MA).…”

Section: Methodsmentioning

confidence: 99%

Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction

Kienesberger

Pulinilkunnil

Sung

et al. 2012

Molecular and Cellular Biology

Self Cite

100

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“…Akt could stimulate TIMP-1 expression in erythroid cells (Kadri et al 2005). PI3Kγ, the molecule upstream of Akt, was proved to inhibit the expression and activity of MMP-2 and MT1-MMP induced by biomechanical stress (Guo et al 2010). Akt2 inhibited MMP-9 expression while stimulated TIMP-1 expression by enhancing phosphorylation of FoxO1 in cultured VSMCs (Shen et al 2013).…”

Section: Discussionmentioning

confidence: 99%

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Chen

Zhao

Jin

et al. 2016

AGE

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Testosterone deficiency is associated with a higher incidence of cardiovascular diseases in men. However, its effect on cell senescence, which plays a causal role in vascular aging, remains unclear. Here, we tested the hypothesis that testosterone alleviated vascular smooth muscle cell (VSMC) senescence and collagen synthesis via growth arrest-specific protein 6 (Gas6)/Axl-and Akt/FoxO1a-dependent pathways. Testosterone significantly ameliorated angiotensin IIinduced VSMC senescence and collagen overexpression. In addition, testosterone inhibited angiotensin IIinduced matrix metalloproteinase-2 (MMP-2) activity, which played a pivotal role in facilitating age-related collagen deposition. Testosterone increased the expression of tissue inhibitor of metalloproteinase-2 but decreased the expression of MMP-2 and membrane type-1 metalloproteinase which contributed to increase MMP-2 activity. The effects on VSMCs senescence and collagen synthesis were mediated by restoration of angiotensin II-induced downregulation of Gas6 and Axl expression and a subsequent reduction of Akt and FoxO1a phosphorylation. The effects of testosterone were reversed by a Gas6 blocker, AxlFc, and a specific inhibitor of Axl, R428. Treatment of VSMCs with PI3K inhibitor LY294002 abrogated the downregulating effect of testosterone on MMP-2 activity. Furthermore, when FoxO1a expression was silenced by using a specific siRNA, the inhibitory effect of testosterone on MMP-2 activity was revered as well, that indicated this process was Akt/FoxO1a dependence. Taken together, Gas6/Axl and Akt/ FoxO1a were involved in protective effects of testosterone on VSMCs senescence and collagen synthesis. Our results provide a novel mechanism underlying the protective effect of testosterone on vascular aging and may serve as a theoretical basis for testosterone replacement therapy.

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“…7,22 ACE2KO mice were treated with the AT 1 R blocker irbesartan (50 mg/kg per day) 21 or the antioxidant and NADPH oxidase inhibitor apocynin (240 mg/kg per day) 23 in the drinking water, and in parallel experiments, ACE2KO mice were implanted with miniosmotic pumps to deliver Ang 1-7 (24 g/kg per hour; Bachem).…”

Section: Pressure-overloadmentioning

confidence: 99%

Cardioprotective Effects Mediated by Angiotensin II Type 1 Receptor Blockade and Enhancing Angiotensin 1-7 in Experimental Heart Failure in Angiotensin-Converting Enzyme 2–Null Mice

Patel

Bodiga²,

Fan³

et al. 2012

Hypertension

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Abstract-Loss of angiotensin (Ang)-converting enzyme 2 (ACE2) and inability to metabolize Ang II to Ang 1-7 perpetuate the actions of Ang II after biomechanical stress and exacerbate early adverse myocardial remodeling. Ang receptor blockers are known to antagonize the effect of Ang II by blocking Ang II type 1 receptor (AT 1 R) and also by upregulating the ACE2 expression. We directly compare the benefits of AT 1 R blockade versus enhancing Ang 1-7 action in pressure-overload-induced heart failure in ACE2 knockout mice. AT 1 R blockade and Ang 1-7 both resulted in marked recovery of systolic dysfunction in pressure-overloaded ACE2-null mice. Similarly, both therapies attenuated the increase in NADPH oxidase activation by downregulating the expression of Nox2 and p47 phox subunits and also by limiting the p47 phox phosphorylation. Biomechanical stress-induced increase in protein kinase C-␣ expression and phosphorylation of extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3, Akt, and glycogen synthase kinase 3␤ were normalized by irbesartan and Ang 1-7. Ang receptor blocker and Ang 1-7 effectively reduced matrix metalloproteinase 2 activation and matrix metalloproteinase 9 levels. Ang II-mediated cellular effects in cultured adult cardiomyocytes and cardiofibrolasts isolated from pressure-overloaded ACE2-null hearts were inhibited to similar degree by AT 1 R blockade and stimulation with Ang 1-7. Thus, treatment with the AT 1 R blocker irbesartan and Ang 1-7 prevented the cardiac hypertrophy and improved cardiac remodeling in pressure-overloaded ACE2-null mice by suppressing NADPH oxidase and normalizing pathological signaling pathways. Key Words: renin-angiotensin system Ⅲ angiotensin 1-7 Ⅲ angiotensin-converting enzyme 2 Ⅲ NADPH oxidase Ⅲ AT 1 receptor Ⅲ heart failure Ⅲ signaling S everal lines of experimental and clinical evidence implicate a key role for the renin-angiotensin system in the pathophysiology of a number of cardiovascular diseases, such as myocardial infarction, hypertension, and heart failure. 1,2Angiotensin II (Ang II), acting via the Ang II type 1 receptor (AT 1 R) and Ang II type 2 receptor, modulates production of reactive oxygen species (ROS), impairing myocardial contractility and extracellular matrix remodeling, thereby negatively impacting on heart function.3 Angiotensin-converting enzyme 2 (ACE2), a homologue of angiotensin-converting enzyme, is a monocarboxypeptidase that metabolizes Ang II to yield angiotensin 1-7 (Ang 1-7) and lowers the Ang II/Ang 1-7 ratio.4-9 Ang II receptor blockers that selectively antagonize the AT 1 R became a valid alternative approach to interfere with the renin-angiotensin system axis and also upregulates ACE2, resulting in the generation of Ang 1-7. 10,11 Ang 1-7 acts on the Mas receptor and plays an important role in counteracting the actions of Ang II. 12-18Ang II-mediated oxidative stress, cardiac hypertrophy, contractile dysfunction, and fibrosis are exacerbated in ACE2-deficient mice, 5,7 whereas recombinant ...

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Loss of PI3Kγ Enhances cAMP-Dependent MMP Remodeling of the Myocardial N-Cadherin Adhesion Complexes and Extracellular Matrix in Response to Early Biomechanical Stress

Cited by 53 publications

References 59 publications

Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction

Myocardial ATGL Overexpression Decreases the Reliance on Fatty Acid Oxidation and Protects against Pressure Overload-Induced Cardiac Dysfunction

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

Cardioprotective Effects Mediated by Angiotensin II Type 1 Receptor Blockade and Enhancing Angiotensin 1-7 in Experimental Heart Failure in Angiotensin-Converting Enzyme 2–Null Mice

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