Abstract

Background: Transient Receptor Potential (TRP) channel stimulation induces the up-regulation of several downstream mediators that are well understood to be cardioprotective in response to ischemic injury in the heart. However, since the discovery of this cardioprotective pathway is completely novel in nature, the extent to which it is modified in the setting of diabetes presents an intriguing translational interest. We hypothesized that the TRP-induced upregulation of this cardioprotective axis is compromised in diabetes.

Methods: CMs isolated from normal and diabetic mice were treated with the TRPA1 agonist, AITC, or the TRPV1 agonist, capsaicin, in the presence or absence of TRPA1, TRPV1, Akt, eNOS or PKCε inhibitors. Nitric oxide (NO) and nitrite levels were observed utilizing confocal microscopy and the Griess assay method, respectively.

Results: AITC induced NO production through a pathway dependent on Akt and eNOS whereas capsaicin elicited NO formation through a pathway dependent upon the presence of PKCε. Furthermore, the formation of nitric oxide in the diabetic model was diminished to a significant extent. TRPA1 and TRPV1 activation stimulated nitric oxide production in diabetic CMs, but to a significantly lesser degree.

Conclusions: The extent to which TRPA1 and TRPV1 activation turns on the cardioprotective axis is severely compromised in diabetic CMs. This may, in part, contribute to the significant worsening of cardiac function observed in diabetes following ischemic events in the heart.

Modified Abstract

The extent to which TRP channel-induced cardioprotection is modified in the setting of diabetes presents an intriguing clinical interest. We hypothesized that the TRP-induced upregulation of this cardioprotective axis is compromised in diabetes. We found that AITC induced NO production through a pathway dependent upon Akt and eNOS, whereas capsaicin worked through a pathway dependent upon the presence of PKCε. Furthermore, activation of TRPA1 and TRPV1 stimulated nitric oxide production in diabetic CMs, but to a significantly lesser degree. Therefore, the extent to which TRPA1 and TRPV1 activation turns on the cardioprotective axis is severely compromised in diabetic CMs. This may, in part, contribute to the significant worsening of cardiac function observed in diabetes following ischemic events in the heart.

Research Category

Biomedical Sciences

Primary Author's Major

Biology

Mentor #1 Information

Mr. Spencer Andrei

Mentor #2 Information

Ms. Manasi Agrawal

Mentor #3 Information

Ms. Monica Ghosh

Mentor #4 Information

Dr. Derek Damron

Presentation Format

Poster

Start Date

21-3-2017 1:00 PM

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Poster

Research Area

Cardiovascular Diseases | Diseases | Medicine and Health Sciences

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Mar 21st, 1:00 PM

Delineating a Cardioprotective Pathway for TRP Channel-Induced Nitric Oxide Production in Diabetic Cardiomyocytes

Background: Transient Receptor Potential (TRP) channel stimulation induces the up-regulation of several downstream mediators that are well understood to be cardioprotective in response to ischemic injury in the heart. However, since the discovery of this cardioprotective pathway is completely novel in nature, the extent to which it is modified in the setting of diabetes presents an intriguing translational interest. We hypothesized that the TRP-induced upregulation of this cardioprotective axis is compromised in diabetes.

Methods: CMs isolated from normal and diabetic mice were treated with the TRPA1 agonist, AITC, or the TRPV1 agonist, capsaicin, in the presence or absence of TRPA1, TRPV1, Akt, eNOS or PKCε inhibitors. Nitric oxide (NO) and nitrite levels were observed utilizing confocal microscopy and the Griess assay method, respectively.

Results: AITC induced NO production through a pathway dependent on Akt and eNOS whereas capsaicin elicited NO formation through a pathway dependent upon the presence of PKCε. Furthermore, the formation of nitric oxide in the diabetic model was diminished to a significant extent. TRPA1 and TRPV1 activation stimulated nitric oxide production in diabetic CMs, but to a significantly lesser degree.

Conclusions: The extent to which TRPA1 and TRPV1 activation turns on the cardioprotective axis is severely compromised in diabetic CMs. This may, in part, contribute to the significant worsening of cardiac function observed in diabetes following ischemic events in the heart.