Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

Ben‐Zvi, Danny; Savion, Naphtali; Kolodgie, Frank D.; Simon, Amos J.; Fisch, Sudeshna; Schäfer, Katrin; Bachner‐Hinenzon, Noa; Cao, Xin; Gertler, Arieh; Solomon, Gili; Kachel, Erez; Raanani, Ehud; Lavee, Jacob; Emeth, Shlomo Kotev; Virmani, Renu; Schöen, Frederick J.; Schneiderman, Jacob

doi:10.1161/jaha.116.003474

Cited by 23 publications

(18 citation statements)

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“…Cardiomyocyte leptin, which activates MMPs and increases ROS production, promotes TGFβ synthesis and activation via paracrine pathways[ 27 ]. Within a similar context, we have recently demonstrated that locally synthesized leptin induced TGFβ expression in aortic wall SMCs, which in turn drove local medial degeneration and aneurysm formation in ApoE -/- mice[ 28 ]. Furthermore, TGFβ mediates apoptosis and promotes myocardial fibrosis through epithelial and endothelial cell trans-differentiation to mesenchymal cells, and enhances ECM synthesis through Smad3 dependent pathways[ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Cardiac leptin overexpression in the context of acute MI and reperfusion potentiates myocardial remodeling and left ventricular dysfunction

Kain

Simon

Greenberg³

et al. 2018

PLoS ONE

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BackgroundAcute MI induces leptin expression in the heart, however the role of myocardial leptin in cardiac ischemia and reperfusion (IR) remains unknown. To shed light on the effects of elevated levels of leptin in the myocardium, we overexpressed cardiac leptin and assessed local remodeling and myocardial function in this context.Methods and resultsCardiac leptin overexpression was stimulated in mice undergoing IR by a single intraperitoneal injection of leptin antagonist (LepA). All mice exhibited a normal pattern of body weight gain. A rapid, long-term upregulation of leptin mRNA was demonstrated in the heart, adipose, and liver tissues in IR/LepA-treated mice. Overexpressed cardiac leptin mRNA extended beyond postoperative day (POD) 30. Plasma leptin peaked 7.5 hours postoperatively, especially in IR/LepA-treated mice, subsiding to normal levels by 24 hours. On POD-30 IR/LepA-treated mice demonstrated cardiomyocyte hypertrophy and perivascular fibrosis compared to IR/saline controls. Echocardiography on POD-30 demonstrated eccentric hypertrophy and systolic dysfunction in IR/LepA. We recorded reductions in Ejection Fraction (p<0.001), Fraction Shortening (p<0.01), and Endocardial Fraction Area Change (p<0.01), and an increase in Endocardial Area Change (p<0.01). Myocardial remodeling in the context of IR and cardiac leptin overexpression was associated with increased cardiac TGFβ ligand expression, activated Smad2, and downregulation of STAT3 activity.ConclusionsCardiac IR coinciding with increased myocardial leptin synthesis promotes cardiomyocyte hypertrophy and fibrosis and potentiates myocardial dysfunction. Plasma leptin levels do not reflect cardiac leptin synthesis, and may not predict leptin-related cardiovascular morbidity. Targeting cardiac leptin is a potential treatment for cardiac IR damage.

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Section: Discussionmentioning

confidence: 99%

Cardiac leptin overexpression in the context of acute MI and reperfusion potentiates myocardial remodeling and left ventricular dysfunction

Kain

Simon

Greenberg³

et al. 2018

PLoS ONE

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“…Aneurysms in this model have some classical features of human AAA, such as ECM degeneration, MMP up-regulation, and macrophage infiltration. Aortic dissections and hematomas have been reported in this model but not aortic rupture [ 65 ] ( Table 1 ). This most likely reflects the limited study of this model, since AngII has been widely reported to induce aortic rupture.…”

Section: Mouse Models Of Aaamentioning

confidence: 98%

“…Another modification of the AngII- ApoE -/- AAA model involved peri-aortic application of leptin [ 65 ]. Aneurysms in this model have some classical features of human AAA, such as ECM degeneration, MMP up-regulation, and macrophage infiltration.…”

Section: Mouse Models Of Aaamentioning

confidence: 99%

Risk Factors and Mouse Models of Abdominal Aortic Aneurysm Rupture

Krishna

Morton

et al. 2020

IJMS

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Abdominal aortic aneurysm (AAA) rupture is an important cause of death in older adults. In clinical practice, the most established predictor of AAA rupture is maximum AAA diameter. Aortic diameter is commonly used to assess AAA severity in mouse models studies. AAA rupture occurs when the stress (force per unit area) on the aneurysm wall exceeds wall strength. Previous research suggests that aortic wall structure and strength, biomechanical forces on the aorta and cellular and proteolytic composition of the AAA wall influence the risk of AAA rupture. Mouse models offer an opportunity to study the association of these factors with AAA rupture in a way not currently possible in patients. Such studies could provide data to support the use of novel surrogate markers of AAA rupture in patients. In this review, the currently available mouse models of AAA and their relevance to the study of AAA rupture are discussed. The review highlights the limitations of mouse models and suggests novel approaches that could be incorporated in future experimental AAA studies to generate clinically relevant results.

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“…Leptin can contribute to activation of the sympathetic nervous system and renin‐angiotensin system in obesity and to both sodium retention and cardiac fibrosis . Leptin is not merely a marker of obesity; it exerts important effects, as is evidenced by the fact that the neurohormonal activation and coronary vascular abnormalities in diet‐induced obesity are blocked by synthetic leptin antagonists …”

Section: Effects Of Leptin On Heart Failure With a Preserved Ejectionmentioning

confidence: 99%

Do sodium‐glucose co‐transporter‐2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis

Packer

2018

Diabetes Obesity Metabolism

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Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of serious heart failure events in patients with type 2 diabetes, but little is known about mechanisms that might mediate this benefit. The most common heart failure phenotype in type 2 diabetes is obesity-related heart failure with a preserved ejection fraction (HFpEF). It has been hypothesized that the synthesis of leptin in this disorder leads to sodium retention and plasma volume expansion as well as to cardiac and renal inflammation and fibrosis. Interestingly, leptin-mediated neurohormonal activation appears to enhance the expression of SGLT2 in the renal tubules, and SGLT2 inhibitors exert natriuretic actions at multiple renal tubular sites in a manner that can oppose the sodium retention produced by leptin. In addition, SGLT2 inhibitors reduce the accumulation and inflammation of perivisceral adipose tissue, thus minimizing the secretion of leptin and its paracrine actions on the heart and kidneys to promote fibrosis. Such fibrosis probably contributes to the impairment of cardiac distensibility and glomerular function that characterizes obesity-related HFpEF. Ongoing clinical trials with SGLT2 inhibitors in heart failure are positioned to confirm or refute the hypothesis that these drugs may favourably influence the course of obesity-related HFpEF by their ability to attenuate the secretion and actions of leptin. K E Y W O R D S antidiabetic drug, cardiovascular disease, SGLT2 inhibitor 1 | INTRODUCTION Sodium-glucose co-transporter-2 (SGLT2) inhibitors have reduced the risk of important heart failure events in patients with type 2 diabetes. In large-scale trials, the risk of heart failure hospitalization was reduced by 35% with empagliflozin and by 33% with canagliflozin. 1,2 2 | POTENTIAL MECHANISMS OF SGLT2 INHIBITORS IN HEART FAILURE Several mechanisms have been proposed to explain the beneficial effects of SGLT2 inhibitors on heart failure. SGLT2 antagonists block sodium reabsorption in the proximal renal tubule, not only by inhibiting SGLT2 but also sodium-hydrogen exchanger (NHE) isoform 3 (NHE3), which is the primary mechanism of sodium reuptake in the kidneys. 3-5 Because of the intimate relationship between SGLT2 and NHE3 in the early segment of the proximal renal tubule, inhibition of one component attenuates the actions of the complex on ion transport. 5 This natriuretic effect accounts for the haemoconcentration seen in clinical trials. 1In addition, the benefit of SGLT2 inhibitors may be related to effects on the heart. First, their antihyperglycaemic effect might reduce cardiac glucotoxicity, 6 although the magnitude of glucoselowering is modest when compared with other antidiabetic agents that do not reduce heart failure events. 7 Second, the mild hyperketonaemia produced by SGLT2 inhibition can shift the fuel supply in the heart from fatty acids to ketones, which may enhance energy efficiency. 8 However, the failing heart already relies on ketone bodies for its metabolism, and this fuel shift may not be adaptive. 9 Third,...

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Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

Cited by 23 publications

References 58 publications

Cardiac leptin overexpression in the context of acute MI and reperfusion potentiates myocardial remodeling and left ventricular dysfunction

Cardiac leptin overexpression in the context of acute MI and reperfusion potentiates myocardial remodeling and left ventricular dysfunction

Risk Factors and Mouse Models of Abdominal Aortic Aneurysm Rupture

Do sodium‐glucose co‐transporter‐2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis

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