Background Therapeutic strategies for preventing paradoxical reperfusion injury after myocardial ischemia are limited. We tested whether central nervous system actions of leptin induce important protective effects on cardiac function and metabolism after myocardial ischemia/reperfusion (I/R) injury, the role of cardiac sympathetic innervation in mediating these effects, and whether there are major sex differences in the cardioprotective effects of chronic central nervous system leptin infusion. Methods and Results Myocardial I/R was induced by temporary ligation of the left descending coronary artery in male and female Wistar rats instrumented with intracerebroventricular cannula in the lateral ventricle. Vehicle or leptin (0.62 μg/h) infusion was started immediately after reperfusion and continued for 28 days using osmotic minipumps connected to the intracerebroventricular cannula. Cardiac function was assessed by echocardiography, ventricular pressures, and exercise performance. Intracerebroventricular leptin treatment markedly attenuated cardiac dysfunction post‐I/R as evidenced by improved ejection fraction (56.7±1.9 versus 22.6%±1.1%), maximal rate of left ventricle rise (11 680±2122 versus 5022±441 mm Hg) and exercise performance (−4.2±7.9 versus −68.2±3.8 Δ%) compared with vehicle‐treated rats. Intracerebroventricular leptin infusion reduced infarct size in females, but not males, when compared with ad‐lib fed or pair‐fed saline‐treated rats. Intracerebroventricular leptin treatment also increased cardiac NAD + /NADH content (≈10‐fold) and improved mitochondrial function when compared with vehicle treatment. Cervical ganglia denervation did not attenuate the cardiac protective effects of leptin after I/R injury. Conclusions These data indicate that leptin, via its central nervous system actions, markedly improves overall heart function and mitochondrial metabolism after I/R injury regardless of sex, effects that are largely independent of cardiac sympathetic innervation.
We examined potential sex differences in appetite and blood pressure (BP) responses to melanocortin-4 receptor (MC4R) blockade in offspring from lean and obese parents. Offspring from normal (N) diet-fed parents were fed N (NN) or high fat (H) diets (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were also fed N (HN) or H diets (HH). Adult male and female offspring were implanted with BP telemetry probes and intracerebroventricular (ICV) cannulae to infuse MC4R antagonist or vehicle. Infusion of the MC4R antagonist SHU-9119 (1 nmol/h) for 7 days caused larger increases in calorie intake and body weight in obese compared to lean offspring. In male offspring, HH and HN groups exhibited higher baseline BP compared to NN and NH, and HH showed greater reduction in BP during SHU-9119 infusion. In female offspring, HH also showed higher baseline BP and greater reduction in BP during MC4R blockade. SHU-9119 reduced heart rate in all groups, but reductions were more pronounced in offspring from lean parents. Combined α and β-adrenergic blockade reduced BP more in male HH offspring compared to NN controls. Losartan reduced BP more in male NH, HN and HH offspring compared to NN controls. Losartan and α and β-adrenergic blockade reduced BP similarly in all female groups. These results suggest that endogenous MC4R activity contributes to elevated BP in obese offspring from obese parents. Our findings also indicate important sex differences in the mechanisms of BP control in male and female offspring of obese parents.
We examined the impact of parental obesity on offspring blood pressure (BP) regulation and cardiovascular responses to stress. Offspring from normal (N) diet-fed C57BL/6J parents were fed either N (NN) or a high-fat (H) diet (NH) from weaning until adulthood. Offspring from obese H diet-fed parents were also fed N (HN) or H diet (HH). Body weight, calorie intake, and fat mass were measured at 22 wk of age when cardiovascular phenotyping was performed. Male and female HH offspring were 15% heavier than NH and 70% heavier than NN offspring. Male HH and HN offspring had elevated BP (121 ± 2 and 115 ± 1 mmHg, by telemetry) compared with male NH and NN offspring (108 ± 6 and 107 ± 3 mmHg, respectively) and augmented BP responses to angiotensin II, losartan, and hexamethonium. Male HH and HN offspring also showed increased BP responses to air-jet stress (37 ± 2 and 38 ± 2 mmHg) compared with only 24 ± 3 and 25 ± 3 mmHg in NH and NN offspring. Baseline heart rate (HR) and HR responses to air-jet stress were similar among groups. In females, BP and cardiovascular responses to stress were similar among all offspring. Male H diet-fed offspring from obese H diet-fed purinoreceptor 7-deficient (HH-P2X7R-KO) parents had normal BP that was similar to control NN-P2X7R-KO offspring from lean parents. These results indicate that parental obesity leads to increased BP and augmented BP responses to stress in their offspring in a sex-dependent manner, and the impact of parental obesity on male offspring BP regulation is markedly attenuated in P2X7R-KO mice.
Transient receptor potential channel 6 (TRPC6) is a nonselective cation channel belonging to the TRP ion channel family and expressed in vascular smooth muscle cells. TRPC6 regulates calcium influx in response to vascular wall mechanical stretch. A previous study reported that TRPC6 is critical for the myogenic response of the middle cerebral artery (MCA). Impaired MCA myogenic response is implicated in cerebral blood flow dysfunction and may promote cognitive deficits. In this study, we investigated whether TRPC6 contributes to the MCA myogenic response at pressure range (from 40 to 180 mmHg) in 12-week-old male wild-type (WT) and whole-body TRPC6 knock-out (TRPC6 KO) mice (n=5-8). Cognitive function (spatial learning and reference memory) was examined at 22 weeks of age using the Morris water maze test. Myogenic response in MCA was similar in WT and TRPC6 KO mice when perfusion pressure was increased from 40 to 80 mmHg. At higher pressures (>120 mmHg), however, TRPC6 KO mice displayed significantly reduced myogenic response compared to WT mice (3 % less of myogenic tone in TRPC6 KO compared to WT) which was further exacerbated when perfusion pressure was increased to 180 mmHg (9 % less of myogenic tone in TRPC6 KO compared to WT). There were no significant differences in wall thickness, wall-to-lumen ratio, vascular distensibility, incremental distensibility, or elastic modulus curves in MCA between WT and TRPC6 KO mice. Compared to WT mice, TRPC6 KO mice displayed similar spatial learning curves after 4 days of training but showed significantly impaired reference memory (14±1 % vs 29±4 % in the target quadrant) and reduced frequency (1.0±0.3 vs 2.1±0.4 in the target area crossing) compared to WT. These findings suggest that TRPC6 deficiency impairs myogenic response at higher perfusion pressures and spatial memory, even at a young age. (AG050049 (F.F), AG057842 (F.F), AG079336 (F.F), NIDDK R00DK113280, R01DK121411, NIGMS P20GM104357 and NIGMS U54GM115428) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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