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Abstract: PO1778

Follistatin Is a Potential Novel Therapeutic Agent for Essential Hypertension

Session Information

Category: Hypertension and CVD

  • 1401 Hypertension and CVD: Epidemiology, Risk Factors, and Prevention

Authors

  • Kuganathan, Ann, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  • Leal, Marcos Soares, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  • Lu, Chao, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  • Gao, Bo, McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  • Dickhout, Jeffrey G., McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
  • Krepinsky, Joan C., McMaster University Faculty of Health Sciences, Hamilton, Ontario, Canada
Background

Follistatin (FST) is an inhibitor of several members of the profibrotic TGFb superfamily. It is highly effective at neutralizing activins, without activity against TGFb1 itself. Activins are known to induce inflammation, oxidative stress and fibrosis, all of which contribute to the vascular dysfunction characteristic of hypertension (HTN). We previously showed that FST inhibits kidney fibrosis, improves kidney function and lowers blood pressure (BP) in a hypertensive chronic kidney disease mouse model. While this is a model of secondary HTN, here we seek to analyze the efficacy of FST in improving BP and vascular structure and function in a model of essential HTN.

Methods

Telemeters were implanted in the abdominal aorta of spontaneously hypertensive rats (SHR), a model of essential HTN, and normotensive control Wistar Kyoto (WKY) rats for wireless BP monitoring. Rats were treated with 0.075mg/kg FST or vehicle IP every other day from 12-20 weeks of age (8 weeks). BP was recorded weekly. First branch mesenteric arteries were harvested for analysis of vascular function using myography, assessed for oxidative stress by DHE, or formalin fixed for IHC.

Results

By the end of the study, FST significantly lowered both systolic and diastolic BP in SHRs (200 +/- 9 over 132 +/- 4 mmHg in control and 189 +/- 2 over 123 +/- 2 mmHg in FST-treated SHRs, P < 0.04 and P < 0.03 respectively). SHR vessels showed increased contractility with the a1 adrenergic agonist phenylephrine, which was attenuated by FST. Impaired endothelium-dependent relaxation in SHR vessels was also improved by FST. Structurally, FST-treated vessels had less collagen deposition, assessed by Trichrome, which was accompanied by a reduction in medial thickness. Increased oxidative stress seen in SHR vessels was inhibited by FST.

Conclusion

FST lowers BP in SHR with established HTN, at least in part by reducing vascular oxidative stress and medial thickening. This manifests as improved vascular function, with decreased hypersensitivity to contractile agents and improved endothelial function. Future work will identify the effects of FST on inflammation, and the role of specific activins in essential HTN.

Funding

  • Private Foundation Support