Deletion of the β2-adrenergic receptor prevents the development of cardiomyopathy in mice

Fajardo, Giovanni; Zhao, Mingming; Urashima, Takashi; Farahani, Sara Jalali; Hu, Dong‐Qing; Reddy, Sushma; Bernstein, Daniel

doi:10.1016/j.yjmcc.2013.07.016

Cited by 37 publications

(23 citation statements)

References 49 publications

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“…In this regard, some studies using β2-KO models indicate that β2 activation can be toxic, not protective as generally thought. 67,68 Increased β2 effects in nonmyocytes, such as fibroblast proliferation, could explain maladaptive effects of β2 activation.…”

Section: Discussionmentioning

confidence: 99%

Adrenergic Receptors in Individual Ventricular Myocytes

Myagmar

Flynn

Cowley

et al. 2017

Circulation Research

104

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Rationale It is unknown if every ventricular myocyte expresses all 5 of the cardiac adrenergic receptors (ARs), beta-1, beta-2, beta-3, alpha-1A, and alpha-1B. The beta-1 and beta-2 are thought to be the dominant myocyte ARs. Objective Quantify the 5 cardiac ARs in individual ventricular myocytes. Methods and Results We studied ventricular myocytes from wild type mice, mice with alpha-1A and alpha-1B knockin reporters, and beta-1 and beta-2 knockout mice. Using individual isolated cells, we measured knockin reporters, mRNAs, signaling (phosphorylation of ERK and phospholamban), and contraction. We found that the beta-1 and alpha-1B were present in all myocytes. The alpha-1A was present in 60%, with high levels in 20%. The beta-2 and beta-3 were detected in only about 5% of myocytes, mostly in different cells. In intact heart, 30% of total beta-ARs were beta-2 and 20% were beta-3, both mainly in nonmyocytes. Conclusion The dominant ventricular myocyte ARs present in all cells are the beta-1 and alpha-1B. The beta-2 and beta-3 are mostly absent in myocytes but are abundant in nonmyocytes. The alpha-1A is in just over half of cells, but only 20% have high levels. Four distinct myocyte AR phenotypes are defined: 30% of cells with beta-1 and alpha-1B only; 60% that also have the alpha-1A; and 5% each that also have the beta-2 or beta-3. The results raise cautions in experimental design, such as receptor overexpression in myocytes that do not express the AR normally. The data suggest new paradigms in cardiac adrenergic signaling mechanisms.

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Section: Discussionmentioning

confidence: 99%

Adrenergic Receptors in Individual Ventricular Myocytes

Myagmar

Flynn

Cowley

et al. 2017

Circulation Research

104

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“…C57BL/6J mice as previously published 29 . Briefly, mice were anesthetized with pentobarbital sodium (100 mg per kg IP).…”

Section: Methodsmentioning

confidence: 99%

Epicardial FSTL1 reconstitution regenerates the adult mammalian heart

Wei

Serpooshan

Hurtado

et al. 2015

Nature

Self Cite

415

391

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The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.

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“…The authors postulate that the role of G 1α-2 in fibroblasts as opposed to cardiomyocytes may be the driving force behind these phenotypes (43). To complicate the story even more, recent models have demonstrated reverse phenotypes for the role of β 1 AR and β 2 AR in heart failure whereby β 1 AR is cardioprotective and β 2 AR promotes cardiotoxicity (48). As a result, in addition to cell and disease specific contexts, the balance between β 1 AR and β 2 AR expression may contribute to the relative role of these receptors in the pathogenesis of heart failure.…”

Section: The Contribution Of Mir-30 and The β-Adrenergic Pathway Towamentioning

confidence: 99%

Sarco“MiR” friend or foe: a perspective on the mechanisms of doxorubicin-induced cardiomyopathy

Saddic

Muehlschlegel

2016

Annals of Translational Medicine

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Anthracyclines are a class of chemotherapeutics used to treat a variety of human cancers including both solid tumors such as breast, ovarian, and lung, as well as malignancies of the blood including leukemia and lymphoma. Despite being extremely effective anti-cancer agents, the application of these drugs is offset by side effects, most notably cardiotoxicity. Many patients treated with doxorubicin (DOX), one of the most common anthracyclines used in oncology, will develop radiographic signs and/or symptoms of cardiomyopathy. Since more and more patients treated with these drugs are surviving their malignancies and manifesting with heart disease, there is particular interest in understanding the mechanisms of anthracycline-induced injury and developing ways to prevent and treat its most feared complication, heart failure. MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of mRNAs. Since miRNAs can regulate many mRNAs in a single network they tend to play a crucial role in the pathogenesis of several diseases, including heart failure. Here we present a perspective on a recent work by Roca-Alonso and colleagues who demonstrate a cardioprotective function of the miR-30 family members following DOX-induced cardiac injury. They provide evidence for direct targeting of these miRNAs on key elements of the β-adrenergic pathway and further show that this interaction regulates cardiac function and apoptosis. These experiments deliver fresh insights into the biology of toxin-induced cardiomyopathy and suggest the potential for novel therapeutic targets.

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Deletion of the β2-adrenergic receptor prevents the development of cardiomyopathy in mice

Cited by 37 publications

References 49 publications

Adrenergic Receptors in Individual Ventricular Myocytes

Adrenergic Receptors in Individual Ventricular Myocytes

Epicardial FSTL1 reconstitution regenerates the adult mammalian heart

Sarco“MiR” friend or foe: a perspective on the mechanisms of doxorubicin-induced cardiomyopathy

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