An angiotensin‐converting enzyme (ACE) polymorphism may mitigate the effects of angiotensin‐pathway medications on posttraumatic stress symptoms

Abstract

Angiotensin, which regulates blood pressure may also act within the brain to mediate stress and fear responses. Common antihypertensive medication classes of angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) have been associated with lower PTSD symptoms. Here we examine the rs4311 SNP in the ACE gene, previously implicated in panic attacks, in the relationship between ACE-I/ARB medications and PTSD symptoms. Participants were recruited from outpatient wait rooms between 2006 and March 2014 (n= 803). We examined the interaction between rs4311 genotype and the presence of blood pressure medication on PTSD symptoms and diagnosis. PTSD symptoms were lower in individuals taking ACE-Is or ARBs (N = 776). The rs4311 was associated with PTSD symptoms and diagnosis (N = 3803), as the T-carriers at the rs4311 SNP had significantly greater likelihood of a PTSD diagnosis. Lastly, the rs4311 genotype modified the effect of ACE-Is or ARBs on PTSD symptoms (N = 443; F1,443 = 4.41, P < 0.05). Individuals with the CC rs4311 genotype showed lower PTSD symptoms in the presence of ACE-Is or ARBs. In contrast, T- carriers showed the opposite, such that the presence of ACE-Is or ARBs was associated with higher PTSD symptoms. These data suggest that the renin-angiotensin system may be important in PTSD, as ACE-I/ARB usage associates with lower symptoms. Furthermore, we provide genetic evidence that some individuals are comparatively more benefitted by ACE-Is/ARBs in PTSD treatment. Future research should examine the mechanisms by which ACE-Is/ARBs affect PTSD symptoms such that pharmaco-genetically informed interventions may be used to treat PTSD.

Angiotensin type 1a receptors on corticotropin‐releasing factor neurons contribute to the expression of conditioned fear1

“…These results contribute to a growing body of evidence implicating central AT 1 R activity in the expression of conditioned fear and anxiety (Khoury et al, 2012, Marvar et al, 2013, Marinzalda Mde et al, 2014, Shekhar, 2014, Shekhar et al, 2006, Johnson et al, 2013, Nylocks et al, 2015, Saavedra et al, 2006), and identify CRFergic cells as a population on which AT 1 R antagonists may act to create these effects. Further, they indicate that the fear expression-attenuating effects of AT 1 R inactivation may be caused by a decrease in fear memory consolidation (i.e., the transfer of a memory from a short-term to a long-term store in a transcription-dependent manner)—rather than an inability to acquire conditioning—as AT 1a R (+/+) and CRF-AT 1a R (−/−) mice showed similar levels of freezing during auditory fear conditioning, but 24 hours later, CRF-AT 1a R (−/−) mice displayed significantly less overall freezing than wild types.…”

“…However, previous studies by our lab (Khoury et al, 2012, Marvar et al, 2013, Nylocks et al, 2015) and others (Marinzalda Mde et al, 2014, Krause et al, 2011) suggest an important role for this receptor in fear-related pathologies such as PTSD. Our current data extend these findings by demonstrating for the first time that AT 1a Rs on CRF-expressing cells contribute to conditioned fear expression without affecting fear acquisition or baseline anxiety, locomotion, blood pressure, or heart rate.…”

“…However, recent studies in humans and mice have suggested roles for AT 1a R activation in post-traumatic stress disorder (PTSD) and auditory fear conditioning, respectively. For example, treatment of humans with angiotensin receptor blockers (ARBs) has been associated with a decrease in the hyperarousal and intrusive symptoms of PTSD (Khoury et al, 2012, Nylocks et al, 2015). Similarly, either acute or chronic administration of the ARB losartan in mice has been found to enhance the extinction of fear memory, but not fear acquisition or extinction training (Marvar et al, 2013).…”

Autonomic and inflammatory consequences of posttraumatic stress disorder and the link to cardiovascular disease

“…Notably, this reduction in PTSD symptoms was not observed with other classes of blood pressure medications, including ␤-blockers, calcium channel blockers, and diuretics. These clinical data support a role for the RAS in the regulation of stress response in individuals exposed to traumatic stress, and this finding was recently replicated (80). In this same study, genetic evidence for a single nucleotide polymorphism (SNP) in the ACE gene in this PTSD cohort was determined.…”

“…In this same study, genetic evidence for a single nucleotide polymorphism (SNP) in the ACE gene in this PTSD cohort was determined. Differential responses to ACE-Is and ARBs were found in those with the ACE intronic SNP (rs4311), as well as greater symptom improvements in PTSD among those with the CC genotype (80). Although speculative, it is possible that ACE genetic polymorphisms such as SNP (rs4311) may explain the varying individual propensities to develop CVD in this PTSD population.…”