Two Faces of Cardiovascular Actions of Testosterone Dependent on the Presence or Absence of Nitric Oxide Synthases in...

Area of Science:

• Cardiovascular Science
• Endocrinology
• Nephrology

Background:

• Elderly men show reduced nitric oxide (NO) production.
• Testosterone replacement therapy (TRT) is linked to increased cardiovascular (CV) events in elderly men.
• The underlying mechanism for TRT's CV effects remains unclear.

Purpose of the Study:

• To investigate the hypothesis that testosterone exerts harmful CV effects under conditions of reduced NO production.
• To examine the impact of testosterone on cardiovascular outcomes in a mouse model with impaired NO synthesis.

Main Methods:

• Utilized a 2/3 nephrectomized triple nitric oxide synthases (NOS)-knockout mouse model (NX-TKO).
• Compared survival rates, myocardial infarction (MI) incidence, and CV risk factors in NX-TKO and wild-type (NX-WT) mice.
• Administered testosterone to orchiectomized (ORX) mice and assessed aortic relaxation and cardiac gene expression via RNA sequencing.

Main Results:

• Male NX-TKO mice exhibited significantly lower survival rates than NX-WT mice.
• Testosterone treatment worsened survival, MI incidence, and CV risk factors in NX-TKO mice but improved them in NX-WT mice after ORX.
• Testosterone impaired aortic relaxation more severely in TKO mice compared to WT mice, with RNA sequencing suggesting immune and inflammatory mechanisms.

Conclusions:

• Testosterone exacerbates cardiovascular harm, including reduced survival, increased MI, impaired arterial function, and worsened CV risk factors, in the absence of NOS.
• These findings suggest a potential explanation for increased CV events observed with TRT in elderly men with diminished NO production.