Dietary α-Linolenic Acid Counters Cardioprotective Dysfunction in Diabetic Mice: Unconventional PUFA Protection

Abstract

Whether dietary omega-3 (n-3) polyunsaturated fatty acid (PUFA) confers cardiac benefit in cardiometabolic disorders is unclear. We test whether dietary -linolenic acid (ALA) enhances myocardial resistance to ischemia-reperfusion (I-R) and responses to ischemic preconditioning (IPC) in type 2 diabetes (T2D); and involvement of conventional PUFA-dependent mechanisms (caveolins/cavins, kinase signaling, mitochondrial function, and inflammation). Eight-week male C57Bl/6 mice received streptozotocin (75 mg/kg) and 21 weeks high-fat/high-carbohydrate feeding. Half received ALA over six weeks. Responses to I-R/IPC were assessed in perfused hearts. Localization and expression of caveolins/cavins, protein kinase B (AKT), and glycogen synthase kinase-3 β (GSK3β); mitochondrial function; and inflammatory mediators were assessed. ALA reduced circulating leptin, without affecting body weight, glycemic dysfunction, or cholesterol. While I-R tolerance was unaltered, paradoxical injury with IPC was reversed to cardioprotection with ALA. However, post-ischemic apoptosis (nucleosome content) appeared unchanged. Benefit was not associated with shifts in localization or expression of caveolins/cavins, p-AKT, p-GSK3β, or mitochondrial function. Despite mixed inflammatory mediator changes, tumor necrosis factor-a (TNF-a) was markedly reduced. Data collectively reveal a novel impact of ALA on cardioprotective dysfunction in T2D mice, unrelated to caveolins/cavins, mitochondrial, or stress kinase modulation. Although evidence suggests inflammatory involvement, the basis of this “un-conventional” protection remains to be identified.

Whole body hypoxic preconditioning-mediated multiorgan protection in db/db mice via nitric oxide-BDNF-GSK-3β-Nrf2 signaling pathway

“…Indeed, there was a significant decrease in pIC 50 values along with an increase in cardiac injury parameters (CK-MB, cTnT and LDH-1) and apoptotic parameters (bcl-2 and caspase 3) in db/db mice as compared to C57BL/6 mice. These findings suggesting the impairment in cardiovascular functions during long-standing diabetes mellitus are consistent with earlier published studies [ 40 - 42 ].…”

The review of alpha‐linolenic acid: Sources, metabolism, and pharmacology

“…Second, ALA can be used to improve diabetes‐induced damage in other organs. Although adding ALA (10%) to the diet could not improve the myocardial ischemia–reperfusion tolerance of chronic T2D rats, it prevented the harmful effects of ischemic preconditioning and restored functional protection (Russell, Griffith, Naghipour, et al, 2020). ALA (10 μM) could eliminate the inhibitory effect of simulated T2D (glucose+insulin+palmitate) on caveolin‐3 in H9c2 cardiomyoblasts by activating the expression of adenylate cyclase and inhibiting the activity of PKCβ2 (Russell, Griffith, Peart, & Headrick, 2020).…”

Adipokines, Myokines, and Cardiokines: The Role of Nutritional Interventions

“…Conversely, in obese adolescents, omega-3 increased lifestyle interventions diminish insulin resistance, leptin concentrations, and endothelial dysfunction [48]. It is important to note that also the correlation between 3-n PUFA intake and cardio cardiometabolic disorders is not yet completely clarified and for example in obese-diabetic mice dietary-linolenic acid (ALA) enhances cardiac parameters improving inflammatory status, leptin synthesis but does not influence body weight and glycemic status [49]. In another study performed using obese mice, 3-n PUFA supplementation reduced leptin concentrations and inflammation state ameliorating cardiometabolic risk [50].…”