Novel Regulation of Cardiac Metabolism and Homeostasis by the Adrenomedullin-Receptor Activity-Modifying Protein 2 System

Yoshizawa, Takahiro; Sakurai, Takayuki; Kamiyoshi, Akiko; Ichikawa-Shindo, Yuka; Kawate, Hisaka; Iesato, Yasuhiro; Koyama, Teruhide; Uetake, Ryuichi; Yang, Lei; Yamauchi, Akira; Tanaka, Megumu; Toriyama, Yuichi; Igarashi, Kyoko; Nakada, Tsutomu; Kashihara, Toshihide; Yamada, Mitsuhiko; Kawakami, Hayato; Nakanishi, Hiroki; Taguchi, Ryo; Nakanishi, Takashi; Akazawa, Hiroshi; Shindo, Takayuki

doi:10.1161/hypertensionaha.111.00647

Cited by 23 publications

(19 citation statements)

References 50 publications

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“…Interestingly, a recently published study demonstrated that a cardiomyocyte-specific Ramp2 deletion led to a DCM-like phenotype due to mitochondrial dysfunction and irregular calcium handling, which the authors attribute to loss of CLR/AM signaling. 46 Similarly, this study suggests that cardiomyocyte loss of Ramp2 in the Ramp2 −/− Tg mice is likely responsible for the DCM. Moreover, our data demonstrates that neither cardiomyocyte- or vSMC-specific loss of Calcrl during development or conditional Calcrl deletion in adults recapitulate the DCM phenotype observed in the Ramp2 −/− Tg and the aforementioned Ramp2 flox/flox ; α MHC-MerCreMer mice.…”

Section: Discussionsupporting

confidence: 58%

Endothelial Restoration of Receptor Activity–Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy

et al. 2016

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Receptor activity-modifying proteins (RAMPs) serve as oligomeric modulators for numerous G protein-coupled receptors (GPCRs), yet elucidating the physiological relevance of these interactions remains complex. Receptor activity-modifying protein 2 (Ramp2) null mice are embryonic lethal, with cardiovascular developmental defects similar to those observed in mice null for canonical adrenomedullin/calcitonin receptor-like receptor (CLR) signaling. We aimed to genetically rescue the Ramp2−/− lethality in order to further delineate the spatiotemporal requirements for RAMP2 function during development and thereby enable the elucidation of an expanded repertoire of RAMP2 functions with Family B GPCRs in adult homeostasis. Endothelial-specific expression of Ramp2 under the VE-cadherin promoter resulted in the partial rescue of Ramp2−/− mice, demonstrating that endothelial expression of Ramp2 is necessary and sufficient for survival. The surviving Ramp2−/− Tg animals lived to adulthood and developed spontaneous hypotension and dilated cardiomyopathy, which was not observed in adult mice lacking CLR. Yet, the hearts of Ramp2−/− Tg animals displayed dysregulation of Family B GPCRs, including parathyroid hormone and glucagon receptors as well as their downstream signaling pathways. These data suggest a functional requirement for RAMP2 in the modulation of additional GPCR pathways in vivo, which is critical for sustained cardiovascular homeostasis. The cardiovascular importance of RAMP2 extends beyond the endothelium and canonical adrenomedullin/CLR signaling, in which future studies could elucidate novel and pharmacologically-tractable pathways for treating cardiovascular diseases.

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Section: Discussionsupporting

confidence: 58%

Endothelial Restoration of Receptor Activity–Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy

et al. 2016

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“…37,38) PPARα and ERRα are downstream factors of PGC-1α and mainly regulate mitochondrial lipid metabolism (by PPARα), the TCA cycle, and the electron transport chain (by ERRα). 39) In addition, recent studies show that AM regulates mitochondria via cAMP-cAMP response element binding protein (CREB)-PGC-1 pathway in mice, 22,40) and has an antiapoptotic effect against DOX via cAMP-dependent pathway in cultured cardiac myocytes. 30) These results suggest that exogenous AM administration is able to protect the heart via regulation and protection of cardiac mitochondria in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…17) In addition, AM has several functions, including antioxidative, 18,19) anti-inflammatory, 20) and angiogenic effects, 21) as well as acting as a regulator of mitochondrial function. 22) In AM gene knockout (AM KO) mice, homozygotes died in utero with abnormal cardiovascular development, and heterozygotes showed elevated blood pressure. 23) Cardiac hypertrophy and fibrosis were observed in AM KO heterozygotes when subjected to cardiovascular stress.…”

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confidence: 99%

Effects of Adrenomedullin on Doxorubicin-Induced Cardiac Damage in Mice

Yoshizawa

Takizawa

Shimada

et al. 2016

Biological & Pharmaceutical Bulletin

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Doxorubicin (DOX) is one of the best known anticancer drugs, and is used in the treatment of lymphoma, lung cancer, stomach cancer, and a number of other cancers. However, DOX has some serious side effects, the worst being lethal heart failure. Occasionally, its side effects result in the cessation of the anticancer treatment, thus having a serious adverse influence on prognosis. Agents that can be administered as alternative prophylactics or to ameliorate the side effects of DOX will be useful in increasing the safety and efficacy of anticancer therapy. Adrenomedullin (AM) is a peptide hormone secreted by many organs, including the heart; it has an organ-protective effect, including antiapoptotic, anti-inflammatory, and antioxidative stress. Blood AM levels increase with heart failure; endogenic AM has been suggested in order to protect the heart. Furthermore, exogenous AM administration has shown therapeutic effects for heart failure in patients. However, it is unclear whether AM can protect the heart against drug-induced cardiac injury in vivo. The present study was performed in order to investigate the effects of AM on DOX-induced cardiac damage. Male BALB/c mice were treated with DOX and/or AM. Exogenous AM improved the survival ratio of DOXtreated mice. In addition, AM reduced serum lactate dehydrogenase (LDH) levels following DOX treatment. On pathological examination, AM was shown to inhibit DOX-induced cardiac tissue damage, mitochondrial abnormality, and cell death. These findings suggest that AM has a protective effect against DOX-induced cardiac damage.

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“…The critical intracellular second messenger, cAMP, regulates numerous growth and developmental processes in the myocardial cell, including discrete compartments to maintain homeostasis and simultaneously control diverse cellular functions (23). Compared with sham-operated group, the cAMP level in the H-HF rats was decreased.…”

Section: Discussionmentioning

confidence: 99%

Effect of apelin on the cardiac hemodynamics in hypertensive rats with heart failure

Hui

Han

et al. 2014

International Journal of Molecular Medicine

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It is known that apelin has definite protective effects on various cardiovascular diseases; however, the mechanism through which hypertension with heart failure (H-HF) is affected by pyroglutamylated apelin-13 (Pyr-AP13) remain unclear. Thus, in the present study, we investigated the effects of apelin on the cardiac hemodynamics in rats with hypertension and heart failure. In our study, cardiac function, dimensions and histological determination of the fibrosis of rats with two-kidney, one-clip induced hypertension and sham-operated rats were assessed using an echocardiography system and Masson’s trichrome. The infusion of either 5% glucose injection (GS) alone or 5% GS containing Pyr-AP13 as a dose, time-matched design on the cardiac hemodynamics in H-HF rats and sham-operated rats was recorded. For the determination of the effects of potential related proteins on cardiac hemodynamics in the H-HF rats, the animals were divided into 5 groups: i) the sham-operated group (n=8); ii) H-HF (n=8); iii) H-HF with infusion of 0.1 μg dose of Pyr-AP13 (n=8) or 5% glucose (GS) (n=8); iv) H-HF with infusion of 1 μg dose of Pyr-AP13 (n=8) or 5% GS (n=8); and v) H-HF with infusion of 10 μg dose of Pyr-AP13 (n=8) or 5% GS (n=8). The concentration of cyclic adenosine 3′,5′-monophosphate (cAMP) was determined by ELISA. The expression of membrane and cytosolic proteins was evaluated by western blot analysis. Significant cardiac and perivascular fibrosis was observed in the H-HF rats. Following the infusion of Pyr-AP13, the systolic and diastolic function was significantly improved in the cardiac hemodynamic parameters in the H-HF rats treated with Pyr-AP13. The apelin receptor (APJ), which was activated by the exogenous infusion of Pyr-AP13, was partially recycled from the cytoplasm back to the plasma membrane; however, membrane APJ was eventually downregulated in the H-HF rats treated with Pyr-AP13 compared with the sham-operated group rats. Our findings suggested that a complex was formed after Pyr-AP13 combined with cellular membrane APJ receptor. However, the endogenous downregulation of the APJ receptor results in benefits from the exogenous administration of apelin.

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Novel Regulation of Cardiac Metabolism and Homeostasis by the Adrenomedullin-Receptor Activity-Modifying Protein 2 System

Cited by 23 publications

References 50 publications

Endothelial Restoration of Receptor Activity–Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy

Endothelial Restoration of Receptor Activity–Modifying Protein 2 Is Sufficient to Rescue Lethality, but Survivors Develop Dilated Cardiomyopathy

Effects of Adrenomedullin on Doxorubicin-Induced Cardiac Damage in Mice

Effect of apelin on the cardiac hemodynamics in hypertensive rats with heart failure

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