Growth hormone-releasing hormone agonist attenuates vascular calcification in diabetic db/db mice

Hao-Lin Ren; Ruiping Cai; Ruize Xue; Yaoxia Zhang; Qian Xu; Xianyang Zhang; RenZhi Cai; Wei Sha; Andrew V Schally; Ming-Sheng Zhou

doi:10.3389/fcvm.2023.1102525

Growth hormone-releasing hormone agonist attenuates vascular calcification in diabetic db/db mice

Front Cardiovasc Med. 2023 Jan 18:10:1102525. doi: 10.3389/fcvm.2023.1102525. eCollection 2023.

Authors

Hao-Lin Ren¹, Ruiping Cai^{2

3}, Ruize Xue^{2

3}, Yaoxia Zhang^{2

3}, Qian Xu^{2

3}, Xianyang Zhang⁴, RenZhi Cai^{4

5}, Wei Sha⁴, Andrew V Schally^{4

5

6

7}, Ming-Sheng Zhou^{2

3}

Affiliations

¹ Department of Radiology, The First Affiliated Hospital, Dalian Medical University, Dalian, China.
² Science and Research Center, Shenyang Medical College, Shenyang, China.
³ Department of Physiology, Shenyang Medical College, Shenyang, China.
⁴ Veterans Affairs Medical Center, Endocrine, Polypeptide and Cancer Institute, Miami, FL, United States.
⁵ Miami Veterans Affairs Medical Center, South Florida VA Foundation for Research and Education, Miami, FL, United States.
⁶ Divisions of Medical/Oncology and Endocrinology, Department of Pathology, Medicine, Miller School of Medicine, University of Miami, Miami, FL, United States.
⁷ Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, United States.

Abstract

Introduction: Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. VC increases mortality of all-causes. VC is one of most common cardiovascular complications in type II diabetes. So far, no therapy has been proven to be effective in treatment of clinical VC. The present study investigated the therapeutic effects of MR409, an agonistic analog of growth hormone-releasing hormone (GHRH-A), on VC in diabetic db/db mice.

Method and result: Diabetic mice were injected with MR409 subcutaneously every day for 8 weeks. Long-term treatment with MR409 improved serum lipid profile and endothelium-dependent relaxation to acetylcholine, and reduced vascular structural injury in diabetic mice without affecting serum growth hormone level. Echocardiography showed that calcium plaques present in heart valve of diabetic mice disappeared in diabetic mice after treatment with MR409. MR409 inhibited vascular calcium deposition associated with a marked reduction in the expressions of osteogenic-regulated alkaline phosphatase (ALP) and transcription osteogenic marker gene Runx2 in diabetic mice. MR409 also inhibited vascular reactive oxygen species (ROS) generation and upregulated the expressions of anti-calcifying protein Klotho in diabetic mice.

Discussion: Our results demonstrate that GHRH-A MR409 can effectively attenuate VC and heart valve calcification, and protect against endothelial dysfunction and vascular injury in diabetic mice without significantly affecting pituitary-growth hormone axis. The mechanisms may involve upregulation of anti-calcifying protein Klotho and reduction in vascular ROS and the expression of redox sensitive osteogenic genes Runx2 and ALP. GHRH-A may represent a new pharmacological strategy for treatment of VC and diabetics associated cardiovascular complications.

Keywords: diabetes; growth hormone-releasing hormone; oxidative stress; vascular calcification; vascular injury.

Grants and funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. 82270434 and 81970357) to M-SZ and Doctoral Research Foundation of Liaoning Province (2021-BS-286) to RPC.