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6. Novel formylpeptide receptor 1/2 agonist limits hypertension-induced cardiovascular damage.

Author

Singh, Jaideep, Jackson, Kristy L, Fang, Haoyun, Gumanti, Audrey, Claridge, Bethany, Tang, Feng Shii, Kiriazis, Helen, Salimova, Ekaterina, Parker, Alex M, Nowell, Cameron, Woodman, Owen L, Greening, David W, Ritchie, Rebecca H, Head, Geoffrey A, and Qin, Cheng Xue

Subjects
ANGIOTENSIN II, ARTERIAL calcification, CARDIAC hypertrophy, HEART fibrosis, INVECTIVE
Abstract

Aims Formylpeptide receptors (FPRs) play a critical role in the regulation of inflammation, an important driver of hypertension-induced end-organ damage. We have previously reported that the biased FPR small-molecule agonist, compound17b (Cmpd17b), is cardioprotective against acute, severe inflammatory insults. Here, we reveal the first compelling evidence of the therapeutic potential of this novel FPR agonist against a longer-term, sustained inflammatory insult, i.e. hypertension-induced end-organ damage. The parallels between the murine and human hypertensive proteome were also investigated. Methods and results The hypertensive response to angiotensin II (Ang II, 0.7 mg/kg/day, s.c.) was attenuated by Cmpd17b (50 mg/kg/day, i.p.). Impairments in cardiac and vascular function assessed via echocardiography were improved by Cmpd17b in hypertensive mice. This functional improvement was accompanied by reduced cardiac and aortic fibrosis and vascular calcification. Cmpd17b also attenuated Ang II-induced increased cardiac mitochondrial complex 2 respiration. Proteomic profiling of cardiac and aortic tissues and cells, using label-free nano-liquid chromatography with high-sensitivity mass spectrometry, detected and quantified ∼6000 proteins. We report hypertension-impacted protein clusters associated with dysregulation of inflammatory, mitochondrial, and calcium responses, as well as modified networks associated with cardiovascular remodelling, contractility, and structural/cytoskeletal organization. Cmpd17b attenuated hypertension-induced dysregulation of multiple proteins in mice, and of these, ∼110 proteins were identified as similarly dysregulated in humans suffering from adverse aortic remodelling and cardiac hypertrophy. Conclusion We have demonstrated, for the first time, that the FPR agonist Cmpd17b powerfully limits hypertension-induced end-organ damage, consistent with proteome networks, supporting development of pro-resolution FPR-based therapeutics for treatment of systemic hypertension complications. [ABSTRACT FROM AUTHOR]

Published
2024
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8. The pro‐resolving mediator, annexin A1 regulates blood pressure, and age‐associated changes in cardiovascular function and remodeling

Author

Singh, Jaideep, primary, Jackson, Kristy L., additional, Tang, Feng Shii, additional, Fu, Ting, additional, Nowell, Cameron, additional, Salimova, Ekaterina, additional, Kiriazis, Helen, additional, Ritchie, Rebecca H., additional, Head, Geoffrey A., additional, Woodman, Owen L., additional, and Qin, Cheng Xue, additional

Published
2024
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16. Home blood pressure monitoring: methodology, clinical relevance and practical application: a 2021 position paper by the Working Group on Blood Pressure Monitoring and Cardiovascular Variability of the European Society of Hypertension

Author

Parati, Gianfranco, Stergiou, George S., Bilo, Grzegorz, Kollias, Anastasios, Pengo, Martino, Ochoa, Juan Eugenio, Agarwal, Rajiv, Asayama, Kei, Asmar, Roland, Burnier, Michel, De La Sierra, Alejandro, Giannattasio, Cristina, Gosse, Philippe, Head, Geoffrey, Hoshide, Satoshi, Imai, Yutaka, Kario, Kazuomi, Li, Yan, Manios, Efstathios, Mant, Jonathan, McManus, Richard J., Mengden, Thomas, Mihailidou, Anastasia S., Muntner, Paul, Myers, Martin, Niiranen, Teemu, Ntineri, Angeliki, O’Brien, Eoin, Octavio, José Andres, Ohkubo, Takayoshi, Omboni, Stefano, Padfield, Paul, Palatini, Paolo, Pellegrini, Dario, Postel-Vinay, Nicolas, Ramirez, Agustin J., Sharman, James E., Shennan, Andrew, Silva, Egle, Topouchian, Jirar, Torlasco, Camilla, Wang, Ji Guang, Weber, Michael A., Whelton, Paul K., White, William B., and Mancia, Giuseppe

Published
2021
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17. Seasonal variation in blood pressure: Evidence, consensus and recommendations for clinical practice. Consensus statement by the European Society of Hypertension Working Group on Blood Pressure Monitoring and Cardiovascular Variability

Author

Stergiou, George S., Palatini, Paolo, Modesti, Pietro A., Asayama, Kei, Asmar, Roland, Bilo, Grzegorz, de la Sierra, Alejandro, Dolan, Eamon, Head, Geoffrey, Kario, Kazuomi, Kollias, Anastasios, Manios, Efstathios, Mihailidou, Anastasia S., Myers, Martin, Niiranen, Teemu, Ohkubo, Takayoshi, Protogerou, Athanasios, Wang, Jiguang, O’Brien, Eoin, and Parati, Gianfranco

Published
2020
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23. Oxidative approaches to the synthesis of bis-Tetrahydrofuran Annonaceous Acetogenins

Author

Head, Geoffrey Douglas

Subjects
547.592
Abstract

Two bis-THF Annonaceous Acetogenin structures were synthesised, one of which corresponded to the cytotoxic antitumour compound membranacin. Both derived from key epoxide intermediate, which was synthesized via the chiral auxiliary directed oxidative cyclisation of 1,5,9-trienedioate by potassium permanganate. The second THF ring was installed using a Sharpless asymmetric epoxidation and epoxide opening strategy. A number of intermediates were designed with the potential for future library synthesis of natural product analogues. The combination of the permanganate oxidation and Kennedy's perrhenate cyclisation of bis-homoallylic alcohols was used to synthesise simple bis-THF model. This combined strategy allows access to the acetogenin bis-THF core.

Published
2004

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