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. 2022 Apr;10(7):e15212.
doi: 10.14814/phy2.15212.

Pharmacological modulation of prostaglandin E2 (PGE2 ) EP receptors improves cardiomyocyte function under hyperglycemic conditions

Karin J Bosma  1   2 , Monica Ghosh  3 , Spencer R Andrei  1   2 , Lin Zhong  2 , Jennifer C Dunn  1   2 , Valerie F Ricciardi  2 , Juliann B Burkett  4 , Antonis K Hatzopoulos  2   5 , Derek S Damron  3 , Maureen Gannon  1   2   4   5
Affiliations

Pharmacological modulation of prostaglandin E2 (PGE2 ) EP receptors improves cardiomyocyte function under hyperglycemic conditions

Karin J Bosma et al. Physiol Rep. 2022 Apr.

Abstract

Type 2 diabetes (T2D) affects >30 million Americans and nearly 70% of individuals with T2D will die from cardiovascular disease (CVD). Circulating levels of the inflammatory signaling lipid, prostaglandin E2 (PGE2 ), are elevated in the setting of obesity and T2D and are associated with decreased cardiac function. The EP3 and EP4 PGE2 receptors have opposing actions in several tissues, including the heart: overexpression of EP3 in cardiomyocytes impairs function, while EP4 overexpression improves function. Here we performed complementary studies in vitro with isolated cardiomyocytes and in vivo using db/db mice, a model of T2D, to analyze the effects of EP3 inhibition or EP4 activation on cardiac function. Using echocardiography, we found that 2 weeks of systemic treatment of db/db mice with 20 mg/kg of EP3 antagonist, beginning at 6 weeks of age, improves ejection fraction and fractional shortening (with no effect on heart rate). We further show that either EP3 blockade or EP4 activation enhances contractility and calcium cycling in isolated mouse cardiomyocytes cultured in both normal and high glucose. Thus, peak [Ca2+ ]I transient amplitude was increased, while time to peak [Ca2+ ]I and [Ca2+ ]I decay were decreased. These data suggest that modulation of EP3 and EP4 activity has beneficial effects on cardiomyocyte contractility and overall heart function.

Keywords: Type 2 diabetes; contractility; diabetic cardiomyopathy; ejection fraction; prostaglandin receptor.

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Figures

FIGURE 1
FIGURE 1
Contractility and Ca2+ peak amplitude are diminished in adult ventricular cardiomyocytes from db/db mice. (a) Fractional shortening (µm/sec) and (b) intracellular Ca2+ concentration ([Ca2+]i) peak amplitude (340/380 ratio) are significantly attenuated in cardiomyocytes isolated from 4‐month‐old db/db mice compared to db/+ mice. ●, db/+. ◾, db/db. ****p < 0.001 versus db/+. Data were analyzed using Student's t‐test and Bonferroni post hoc analysis. Results are expressed as a fold of the db/+ control. N = 20 cardiomyocytes from five hearts per group
FIGURE 2
FIGURE 2
EP3 blockade improves contractility and Ca2+ cycling in cardiomyocytes. Isolated cardiomyocytes from 4‐month‐old wild‐type mice were cultured in normal glucose (NG) and high glucose (HG). (a) Representative traces of calcium flux (upper panel) and sarcomere length (lower panel) of cardiomyocytes cultured in low glucose, with or without the EP3 antagonist DG‐041. Acute hyperglycemia resulted in significant decreases in (b) fractional shortening, (c) maximal velocity of shortening, (d) maximal velocity of relengthening, and (e) Ca2+ peak amplitude. Additionally, acute hyperglycemia resulted in significant increases in (f) time to peak [Ca2+]I and (G) Ca2+]I decay. Acute treatment with the EP3 antagonist DG‐041 resulted in increased (b) fractional shortening (percent of relaxed sarcomere length), (c) maximum velocity of shortening (‐µm/sec), and (d) maximum velocity of relengthening (+µm/s). EP3 blockade also increased (e) [Ca2+]i peak amplitude (340/380 ratio) and accelerated (f) time to peak [Ca2+]i (s), and (G) [Ca2+]i decay (s). Results are expressed as a fold of the steady‐state baseline for the vehicle‐treated normal glucose control (NG: Control). Same colored symbols represent separate individual cardiomyocytes derived from the same mouse heart. N = 20 cardiomyocytes from five hearts per group. Data were analyzed using a two‐way ANOVA with Tukey multiple comparisons post hoc test. ●: NG control, ⚪: NG DG‐041, ▴: HG control, ▵: HG DG‐041. x = vs NG control, * vs NG control, † vs HG control, $ vs NG DG041. 1 symbol: p < 0.05, 2 symbols: p < 0.01, 3 symbols: p < 0.001, 4 symbols: p < 0.0001
FIGURE 3
FIGURE 3
EP4 activation improves contractility and Ca2+ cycling in cardiomyocytes. Isolated cardiomyocytes from 4‐month‐old wild‐type mice were cultured in normal glucose (NG) and high glucose (HG). (a) Representative traces of calcium flux (upper panel) and sarcomere length (lower panel) of cardiomyocytes cultured in low glucose, with or without the EP4 agonist CAY10598. Acute hyperglycemia resulted in significant decreases in (c) maximal velocity of shortening and (d) maximal velocity of relengthening. Additionally, acute hyperglycemia resulted in significant increase in (f) time to peak [Ca2+]I and (g) Ca2+]I decay. Acute treatment with the EP4 agonist CAY10598 resulted in increased (b) fractional shortening, (c) maximum velocity of shortening, and (d) maximum velocity of relengthening in normal (NG)‐ and high glucose (HG)‐cultured cardiomyocytes. Acute CAY10598 treatment also increased (e) [Ca2+]i peak amplitude and accelerated (f) time to peak [Ca2+]i and (G) [Ca2+]i decay. Results are expressed as a fold of the steady‐state baseline of vehicle‐treated NG control (NG: Control). Data were analyzed using a two‐way ANOVA with Tukey multiple comparisons post hoc test. Statistics: Same colored symbols represent separate individual cardiomyocytes derived from the same heart. N = 15 cardiomyocytes from four hearts per group. ●: NG control, ⚪: NG DG‐041, ▴: HG control, ▵: HG DG‐041. x = vs NG control, * vs NG control, † vs HG control, $ vs NG DG041. 1 symbol: p < 0.05, 2 symbols: p < 0.01, 3 symbols: p < 0.001, 4 symbols: p < 0.0001
FIGURE 4
FIGURE 4
Ptger3 and Ptger4 expression in whole hearts of db/+ and db/db mice. Comparison of Ptger3 and Ptger4 expression in hearts isolated from 8‐week‐old db/+ and db/db after 2 weeks of vehicle (10% DMSO in PBS) or 20 mg/kg DG‐041 treatment. Gene expression was quantified relative to actin and then expressed relative to expression in vehicle‐treated db/+ mice. Results represent mean +/− S.E.M. n = 3–4 mice per group. ●, db/+ treated with vehicle. ◾, db/+ treated with DG‐041. ⚪, db/db treated with vehicle. ◽, db/db treated with DG‐041
FIGURE 5
FIGURE 5
Echocardiography images from vehicle and DG‐041‐treated db/+ and db/db mice. Representative images from transthoracic echocardiography performed on 8‐week‐old (a) db/+ mice treated for 2 weeks with vehicle, (b) db/+ mice treated for 2 weeks with DG‐041, (c) db/db mice treated for 2 weeks with vehicle, and (d) db/db mice treated for 2 weeks with DG‐041. Images were obtained on conscious mice using a Vevo2100 Imaging System
FIGURE 6
FIGURE 6
Cardiac function in vehicle and DG‐041‐treated db/+ and db/db mice. (a) Heart rate, (b) diastolic diameter, (c) diastolic volume, (d) stroke volume, (e) cardiac output, (f) LVAWd, (g) LVAWs, (h) LVIDd, (i) LVAWd, (j) LVAWs, (k) ejection fraction, and (l) fractional shortening in 8‐week‐old db/+ or db/db mice treated with either vehicle or DG‐041 for 2 weeks. Data points represent summarized data from three consecutive cardiac cycles. Summarized data were analyzed via ANOVA followed by Bonferroni post hoc analysis. Results represent mean +/− S.E.M. ●, db/+ treated with vehicle. ◾, db/+ treated with DG‐041. ⚪, db/db treated with vehicle. ◽, db/db treated with DG‐041
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