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Regression of Post-Prandial Cardiac Hypertrophy in Burmese Pythons is Mediated by FoxO1

ABSTRACT: As ambush-hunting predators that consume large prey after long intervals of fasting, Burmese pythons evolved with unique adaptations for regulating organ structure and function. Among these is cardiac hypertrophy that develops within three days following a meal (1, 2), which we previously showed was initiated by circulating growth factors (3). Post-prandial cardiac hypertrophy in pythons also rapidly regresses with subsequent fasting (2); however, the molecular mechanisms that regulate the dynamic cardiac remodeling in pythons during digestion are largely unknown. In this study, we employed a multi-omics approach coupled with targeted molecular analyses to examine remodeling of the python ventricular transcriptome and proteome throughout digestion. We found that forkhead box protein O1 (FoxO1) signaling was suppressed prior to hypertrophy development and then activated with regression, which coincided with decreased and then increased expression, respectively, of FoxO1 transcriptional targets involved in protein degradation. To define the molecular mechanistic role of FoxO1 in hypertrophy regression, we used cultured mammalian cardiomyocytes treated with post-fed python plasma. Hypertrophy regression both in pythons and in vitro coincided with activation of FoxO1-dependent autophagy; however, introduction of a FoxO1-specific inhibitor prevented both regression of cell size and autophagy activation. Finally, to determine if FoxO1 activation could induce regression, we generated an adenovirus expressing a constitutively active FoxO1. FoxO1 activation was sufficient to prevent and reverse post-fed plasma-induced hypertrophy, which was partially prevented by autophagy inhibition. Our results indicate that modulation of FoxO1 activity contributes to the dynamic ventricular remodeling in post-prandial Burmese pythons.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Python Bivittatus

TISSUE(S): Heart, Ventricular Cardiac Muscle Cell

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Thomas Martin

LAB HEAD: Leslie Leinwand

PROVIDER: PXD054079 | Pride | 2024-09-12

REPOSITORIES: Pride

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			Action	DRS
	CCE20220811_TommyMartin_LeinwandLab_PythonHeart_TMTPro16plex_HpHfr10_hfx1.raw	Raw
	CCE20220811_TommyMartin_LeinwandLab_PythonHeart_TMTPro16plex_HpHfr10_hfx2.raw	Raw
	CCE20220811_TommyMartin_LeinwandLab_PythonHeart_TMTPro16plex_HpHfr11_hfx1.raw	Raw
	CCE20220811_TommyMartin_LeinwandLab_PythonHeart_TMTPro16plex_HpHfr11_hfx2.raw	Raw
	CCE20220811_TommyMartin_LeinwandLab_PythonHeart_TMTPro16plex_HpHfr12_hfx1.raw	Raw

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Project description:Background: Vitamin D deficiency is associated with cardiac hypertrophy and heart failure, and vitamin D therapy prevents the progression of cardiac hypertrophy in animal models. Here, we examine whether vitamin D therapy regresses pre-existing cardiac hypertrophy, and prevents the progression to heart failure. Methods and Results: When male Dahl salt-sensitive (DSS) rats are fed a high salt (HS) diet, all rats develop cardiac hypertrophy after 5 weeks (H). Thereafter, rats were treated with vehicle (V), paricalcitol (PC, an active vitamin D analog at 200ng, IP 3x/wk), enalapril (EP, 90ug/day), and PC+EP. All groups were continued on the HS diet and evaluated after 4 weeks of therapy. The PC and PC+EP, but not the V and EP-only groups, showed significant regression of pre-existing cardiac hypertrophy. The signs of decompensated heart failure were evident in the vehicle-treated group; these heart failure parameters significantly improved with PC, EP or PC+EP therapy. The expression of PKCe, which is regulated by Ca2+ and known to stimulate cardiac hypertrophy, was significantly increased in the vehicle group, and PC, EP or PC+EP effectively decreased PKCe activation. We also observed normalization of genetic alterations during progression to heart failure with PC treatment. Conclusions: PC treatment resulted in both the regression of pre-existing cardiac hypertrophy, and the attenuation of the progression to heart failure, compared to improvement in progression to heart failure by EP alone. These beneficial findings in the heart were associated with inhibition of PKCe activation, and reversal of gene alterations. Male Dahl salt-sensitive rats (Harlan Sprague–Dawley, Somerville, NJ) were bred and fed a normal diet until 6 weeks of age. To generate pressure overload cardiac hypertrophy, they were then fed a high salt (6%NaCl) diet for the next 5 weeks. Data for baseline hypertrophic group (H) was obtained at the end of 11 weeks. Among H group animals, they were divided as follows and treated for an additional 4 weeks: 1) continuation of the HS diet with vehicle injection (H+V); 2) continuation of the HS diet with paricalcitol (19-nor-1,25-(OH)2 D2) (PC) (200ng IP 3x/wk) injection (H+PC); 3) continuation of the HS diet with low dose enalapril (EP), an angiotensin-converting enzyme inhibitor, infusion via osmotic pump and vehicle injection (H+EP+V); and 4) continuation of the HS diet with low dose EP infusion via osmotic pump and PC (200ng IP 3x/wk) injection (H+EP+PC). PC was prepared with 95% propylene glycol and 5% ethyl alcohol solution and administered three times a week on Monday, Wednesday, and Friday for 4 consecutive weeks. Vehicle groups received vehicle injections on the same schedule. Two groups of rats were implanted with pumps to deliver EP for 4 weeks. Since the reduction in blood pressure (BP) from high doses of EP would have effects on cardiac hypertrophy and progression to heart failure, we used low dose EP at 90ug/day, a maximum dose that did not significantly decrease BP in these rats, to study the effects of EP and PC that are independent of BP.

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Regression of Post-Prandial Cardiac Hypertrophy in Burmese Pythons is Mediated by FoxO1

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