Abstract: SA-PO351
Deletion of the Gene for Transient Receptor Potential Canonical 1 (TRPC1) Channel Induces Diabetes and Cardiovasculopathy but Paradoxically Prevents the Cardiomyopathy from a High-Fat Diet (HFD)
Session Information
- Hypertension and CVD: Mechanisms
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Hypertension and CVD
- 1403 Hypertension and CVD: Mechanisms
Authors
- Eby, Bonnie, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Lozano, Pedro, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Pennington, Becky, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Lau, Alexander, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Pantalia, Meghan M., University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
- Lau, Kai, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, United States
Background
TRPC1 is key in transducing Ca signal in the hypertrophic response to aortic constriction, but its natural role is unknown..Since +/- & -/- mice are hyperglycemic & since untreated diabetes induces cardiomyopathy, we tested if TRPC1 deficiency creates cardiovascular phenotypes & if 45% HFD aggravates these abnormalities.
Methods
In age-matched wild type, +/- & -/- males, we measured body weights (BW), heart weights (HW) & did echocardiographic studiies at ages 3, 7, 17 & 23 mon. At 7 mon, we measured blood pressure (BP) by tail cuffs & direct intraarterial readings of systolic (S) & diastolic (D) to get mean arterial BP (MABP). We studied aortic relaxation in chamber.
Results
In null mice, HW was 12-13% lighter at 2 mon & 7 mon. At 23 mon, HW remained 19% & HW:BW 23% lower, documenting cardiac hypoplasia. At 7 mon, in null mice, left ventricular (LV) end-diastolic (ED) volume (29 vs 56 μl) was down by 48%, ES volume (3 vs 11 μl) by 73%, stroke volume (26 vs 45 μl) by 42%, & stroke index (SI) (0.8 vs 1.4 µl/g BW) by 44%. Cardiac output (CO)(14 vs 21 ml/min) was 33 % down, as were SBP (113 vs 121 torr), DBP (77 vs 86 torr) & MABP (89 vs 98 torr). Systemic arterial resistance [MABP/CO], was elevated (7 vs 5 torr/ml/min). Pulse pressure was similar. Arterial stiffness [pulse pressure/SI] was up 2 fold as arterial compliance was down by 49%. Aortic relaxation, normal at 2 mon, was reduced at 23 mon in null mice. At 17 mon, LV fractional shortening (FS) was down by 16% in null & by 13% in +/-. LVEF was down by 7% in null. In wild type, HFD x 3 mon reduced FS by 17%, LVEF by 8% & SI by 26%. In contrast, HFD did not alter FS, LVEF, or SI in null mice, as if without TRPC1, the reduced cytosolic Ca blunts the activation of cardiac myocytes by HFD via the signaling pathway of Ca-calcineurin (CN)-NFAT. Indeed, SI in +/- mice with less impaired Ca homeostasis tended to fall with HFD.
Conclusion
Given the blunted cell Ca response to activation in all cells we studied in null mice, these data support the thesis that TRPC1 deficiency attentuates the intracellular CN-NFAT signaling to normal proliferative stimuli, producing cardiac hypoplasia & low CO. The same blunted Ca signaling prevents the cardiomyopathy induced by HFD and seen in wild types.
Funding
- NIDDK Support