Mitochondrial fragmentation in heart failure with preserved ejection fraction: therapeutic potential of the SAMBA molecule

• Grant number: 21/09608-8
• Support type: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): March 01, 2022
• Effective date (End): February 29, 2024
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal researcher: Julio Cesar Batista Ferreira
• Grantee: Itamar Couto Guedes de Jesus
• Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Heart failure (HF) is the leading cause of morbidity and mortality worldwide. Patients with HF are classified into two subgroups: HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). For decades, the majority all scientific attention was focused on the understanding of HFrEF due to of its practical diagnostic criteria and high prevalence of morbidity and mortality among patients, while little progress had being made on the understanding of the HFpEF pathophysiology. Recent epidemiological studies have shown similar mortality/hospitalization incidences and quality of life between HFpEF and HFrEF patients. In fact, HFpEF is accounts for 50% of all HF cases, being more prevalent in women and the elderly population. HFpEF is considered a multiorgan syndrome with multiple comorbidities such as, hypertension, diabetes, and obesity, which favor the structural and hemodynamic changes that are characteristic of the syndrome, such as ventricular remodeling, diastolic dysfunction, exercise intolerance, and reduced longevity. However, despite its increasing prevalence, little is known about the molecular mechanisms involved in the establishment and progression of HFpEF, hindering the development of effective and specific therapeutic strategies for this syndrome. Recently, knowledge about the pathophysiology of HFpEF established that, in addition to the hemodynamic and morphological cardiac disorders associated with the disease, alterations in the number, size and mitochondrial bioenergetics are present in the heart of patients with HFpEF. These associative but clinically relevant data suggest that impairment in mitochondrial dynamics and bioenergetics is involved in the pathophysiology of HFpEF. However, a definitive proof-of-concept aiming to determine the causality between the two phenomena is lacking. Our research group has recently developed a molecule, called SAM²A, which is capable to restore cardiac mitochondrial dynamics and bioenergetics in an experimental model of HFrEF. The SAM²A molecule selectively blocks the inhibitory effect that beta II protein kinase C (²IIPKC) exerts on mitofusin 1 (Mfn1, involved in the mitochondrial fusion process) and, consequently, reverses the mitochondrial fragmentation and cardiac dysfunction observed in animals with HFrEF. In this new proposed study, we will evaluate the profile of protein expression of ²IIPKC and enzymes involved in mitochondrial dynamics, GTPase activity of Mfn1, and the interaction between ²IIPKC and Mfn1 in the heart of animals. We will also evaluate the morphology, oxygen consumption and hydrogen peroxide release of mitochondria isolated from the heart of mice with HFpEF and respective controls. In addition, cardiac function and remodeling, survival, exercise tolerance, and circulating levels of glucose, triglycerides, cholesterol, and brain natriuretic peptide (BNP, HFpEF marker) will be analyzed. HFpEF model will be induced in female mice through a combination of high-fat diet and chronic infusion of Angiotensin II for 12 weeks, generating the same metabolic and hemodynamic stress observed in patients with HFpEF. Treatments with the SAM²A molecule or its vehicle will be carried out through osmotic minipumps, starting in the fourth week after HFpEF induction and lasting for 8 weeks. Findings from this study will accelerate the understanding of the role of mitochondrial dynamics in HFpEF and have direct clinical relevance since our study prioritize the development of a novel mechanistic-based therapy for HFpEF. The multidisciplinary approach of this proposal is illustrated by our collaboration with leaders in their field, which include: Profs. Drs. Daria Mochly-Rosen (Stanford University), Nir Qvit (Bar-llan University, Israel), Dr. Andreza do Bem (UnB) and Marcos R. Chiaratti (UFSCar).